Peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers

ABSTRACT

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/713,157, filed 13 Dec. 2019, which is a continuation of U.S. patentapplication Ser. No. 16/281,790, filed 21 Feb. 2019, now U.S. Pat. No.10,533,041, issued 14 Jan. 2020, which is a continuation of of U.S.patent application Ser. No. 16/101,081, filed 10 Aug. 2018, now U.S.Pat. No. 10,239,925, issued 26 Mar. 2019, which is a continuation ofU.S. patent application Ser. No. 15/980,328, filed 15 May 2018, now U.S.Pat. No. 10,174,089, issued 8 Jan. 2019, which is a continuation of U.S.patent application Ser. No. 15/198,471, filed 30 Jun. 2016, now U.S.Pat. No. 10,000,539, issued 19 Jun. 2018, which claims the benefit ofU.S. Provisional Application Ser. No. 62/187,507, filed 1 Jul. 2015, andGreat Britain Application No. 1511546.2, filed 1 Jul. 2015, the contentof each of these applications is herein incorporated by reference intheir entirety.

This application is also related to PCT/EP2016/065166 filed 29 Jun.2016, the content of which is incorporated herein by reference in itsentirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED AS A COMPLIANT ASCII TEXT FILE(.txt)

Pursuant to the EFS-Web legal framework and 37 CFR §§ 1.821-825 (seeMPEP § 2442.03(a)), a Sequence Listing in the form of an ASCII-complianttext file (entitled “2912919-050024_Sequence_Listing_ST25.txt” createdon 12 Nov. 2021, and 105,654 bytes in size) is submitted concurrentlywith the instant application, and the entire contents of the SequenceListing are incorporated herein by reference.

FIELD

The present invention relates to peptides, proteins, nucleic acids andcells for use in immunotherapeutic methods. In particular, the presentinvention relates to the immunotherapy of cancer. The present inventionfurthermore relates to tumor-associated T-cell peptide epitopes, aloneor in combination with other tumor-associated peptides that can forexample serve as active pharmaceutical ingredients of vaccinecompositions that stimulate anti-tumor immune responses, or to stimulateT cells ex vivo and transfer into patients. Peptides bound to moleculesof the major histocompatibility complex (MHC), or peptides as such, canalso be targets of antibodies, soluble T-cell receptors, and otherbinding molecules.

The present invention relates to several novel peptide sequences andtheir variants derived from HLA class I molecules of human tumor cellsthat can be used in vaccine compositions for eliciting anti-tumor immuneresponses, or as targets for the development ofpharmaceutically/immunologically active compounds and cells.

BACKGROUND OF THE INVENTION

Ovarian Cancer

With an estimated 239 000 new cases in 2012, ovarian cancer is theseventh most common cancer in women, representing 4% of all cancers inwomen. The fatality rate of ovarian cancer tends to be rather highrelative to other cancers of the female reproductive organs, and casefatality is higher in lower-resource settings. As a consequence, ovariancancer is the eighth most frequent cause of cancer death among women,with 152 000 deaths. In 2012, almost 55% of all new cases occurred incountries with high or very high levels of human development; 37% of thenew cases and 39% of the deaths occurred in Europe and North America.Incidence rates are highest in northern and eastern Europe, NorthAmerica, and Oceania, and tend to be relatively low in Africa and muchof Asia. Incidence rates have been declining in certain countries withvery high levels of human development, notably in Europe and NorthAmerica.

The most common ovarian cancers are ovarian carcinomas, which are alsothe most lethal gynecological malignancies. Based on histopathology andmolecular genetics, ovarian carcinomas are divided into five main types:high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous(3%), and low-grade serous carcinomas (<5%), which together account formore than 95% of cases. Much less common are malignant germ cell tumours(dysgerminomas, yolk sac tumours, and immature teratomas) (3% of ovariancancers) and potentially malignant sex cord stromal tumours (1-2%), themost common of which are granulosa cell tumours.

Family history of ovarian cancer accounts for 10% of cases; the risk isincreased 3-fold when two or more first-degree relatives have beenaffected. Women with germline mutations in BRCA1 or BRCA2 have a 30-70%risk of developing ovarian cancer, mainly high-grade serous carcinomas,by age 70 (Risch et al., 2006).

Surgical resection is the primary therapy in early as well as advancedstage ovarian carcinoma. Surgical removal is followed by systemicchemotherapy with platinum analogs, except for very low grade ovariancancers (stage IA, grade 1), where post-operative chemotherapy is notindicated. In advanced stage ovarian cancer, the first line chemotherapycomprises a combination of carboplatin with paclitaxel, which can besupplemented with bevacizumab. The standard treatment forplatinum-resistant ovarian cancers consists of a monotherapy with one ofthe following chemotherapeutics: pegylated liposomal doxorubicin,topotecane, gemcitabine or paclitaxel (S3-Leitlinie maligneOvarialtumore, 2013).

Immunotherapy appears to be a promising strategy to ameliorate thetreatment of ovarian cancer patients, as the presence ofpro-inflammatory tumor infiltrating lymphocytes, especially CD8-positiveT cells, correlates with good prognosis and T cells specific fortumor-associated antigens can be isolated from cancer tissue.

Therefore, a lot of scientific effort is put into the investigation ofdifferent immunotherapies in ovarian cancer. A considerable number ofpre-clinical and clinical studies has already been performed and furtherstudies are currently ongoing. Clinical data are available for cytokinetherapy, vaccination, monoclonal antibody treatment, adoptive celltransfer and immunomodulation.

Cytokine therapy with interleukin-2, interferon-alpha, interferon-gammaor granulocyte-macrophage colony stimulating factor aims at boosting thepatient's own anti-tumor immune response and these treatments havealready shown promising results in small study cohorts.

Phase I and II vaccination studies, using single or multiple peptides,derived from several tumor-associated proteins (Her2/neu, NY-ESO-1, p53,Wilms tumor-1) or whole tumor antigens, derived from autologous tumorcells revealed good safety and tolerability profiles, but only low tomoderate clinical effects.

Monoclonal antibodies that specifically recognize tumor-associatedproteins are thought to enhance immune cell-mediated killing of tumorcells. The anti-CA-125 antibodies oregovomab and abagovomab as well asthe anti-EpCAM antibody catumaxomab achieved promising results in phaseII and III studies. In contrast, the anti-MUC1 antibody HMFG1 failed toclearly enhance survival in a phase III study.

An alternative approach uses monoclonal antibodies to target and blockgrowth factor and survival receptors on tumor cells. Whileadministration of trastuzumab (anti-HER2/neu antibody) and MOv 8 andMORAb-003 (anti-folate receptor alpha antibodies) only conferred limitedclinical benefit to ovarian cancer patients, addition of bevacizumab(anti-VEGF antibody) to the standard chemotherapy in advanced ovariancancer appears to be advantageous.

Adoptive transfer of immune cells achieved heterogeneous results inclinical trials. Adoptive transfer of autologous, in vitro expandedtumor infiltrating T cells was shown to be a promising approach in apilot trial. In contrast, transfer of T cells harboring a chimericantigen receptor specific for folate receptor alpha did not induce asignificant clinical response in a phase I trial. Dendritic cells pulsedwith tumor cell lysate or tumor-associated proteins in vitro were shownto enhance the anti-tumor T cell response upon transfer, but the extentof T cell activation did not correlate with clinical effects. Transferof natural killer cells caused significant toxicities in a phase IIstudy.

Intrinsic anti-tumor immunity as well as immunotherapy are hampered byan immunosuppressive tumor microenvironment. To overcome this obstacleimmunomodulatory drugs, like cyclophosphamide, anti-CD25 antibodies andpegylated liposomal doxorubicin are tested in combination withimmunotherapy. Most reliable data are currently available foripilimumab, an anti-CTLA4 antibody, which enhances T cell activity.Ipilimumab was shown to exert significant anti-tumor effects in ovariancancer patients (Mantia-Smaldone et al., 2012).

Considering the severe side-effects and expense associated with treatingcancer, there is a need to identify factors that can be used in thetreatment of cancer in general and ovarian cancer in particular. Thereis also a need to identify factors representing biomarkers for cancer ingeneral and ovarian cancer in particular, leading to better diagnosis ofcancer, assessment of prognosis, and prediction of treatment success.

Immunotherapy of cancer represents an option of specific targeting ofcancer cells while minimizing side effects. Cancer immunotherapy makesuse of the existence of tumor associated antigens.

The current classification of tumor associated antigens (TAAs) comprisesthe following major groups:

a) Cancer-testis antigens: The first TAAs ever identified that can berecognized by T cells belong to this class, which was originally calledcancer-testis (CT) antigens because of the expression of its members inhistologically different human tumors and, among normal tissues, only inspermatocytes/spermatogonia of testis and, occasionally, in placenta.Since the cells of testis do not express class I and II HLA molecules,these antigens cannot be recognized by T cells in normal tissues and cantherefore be considered as immunologically tumor-specific. Well-knownexamples for CT antigens are the MAGE family members and NY-ESO-1.

b) Differentiation antigens: These TAAs are shared between tumors andthe normal tissue from which the tumor arose. Most of the knowndifferentiation antigens are found in melanomas and normal melanocytes.Many of these melanocyte lineage-related proteins are involved inbiosynthesis of melanin and are therefore not tumor specific butnevertheless are widely used for cancer immunotherapy. Examples include,but are not limited to, tyrosinase and Melan-A/MART-1 for melanoma orPSA for prostate cancer.

c) Over-expressed TAAs: Genes encoding widely expressed TAAs have beendetected in histologically different types of tumors as well as in manynormal tissues, generally with lower expression levels. It is possiblethat many of the epitopes processed and potentially presented by normaltissues are below the threshold level for T-cell recognition, whiletheir over-expression in tumor cells can trigger an anticancer responseby breaking previously established tolerance. Prominent examples forthis class of TAAs are Her-2/neu, survivin, telomerase, or WT1.

d) Tumor-specific antigens: These unique TAAs arise from mutations ofnormal genes (such as β-catenin, CDK4, etc.). Some of these molecularchanges are associated with neoplastic transformation and/orprogression. Tumor-specific antigens are generally able to induce strongimmune responses without bearing the risk for autoimmune reactionsagainst normal tissues. On the other hand, these TAAs are in most casesonly relevant to the exact tumor on which they were identified and areusually not shared between many individual tumors. Tumor-specificity (or-association) of a peptide may also arise if the peptide originates froma tumor- (-associated) exon in case of proteins with tumor-specific(-associated) isoforms.

e) TAAs arising from abnormal post-translational modifications: SuchTAAs may arise from proteins which are neither specific noroverexpressed in tumors but nevertheless become tumor associated byposttranslational processes primarily active in tumors. Examples forthis class arise from altered glycosylation patterns leading to novelepitopes in tumors as for MUC1 or events like protein splicing duringdegradation which may or may not be tumor specific.

f) Oncoviral proteins: These TAAs are viral proteins that may play acritical role in the oncogenic process and, because they are foreign(not of human origin), they can evoke a T-cell response. Examples ofsuch proteins are the human papilloma type 16 virus proteins, E6 and E7,which are expressed in cervical carcinoma.

T-cell based immunotherapy targets peptide epitopes derived fromtumor-associated or tumor-specific proteins, which are presented bymolecules of the major histocompatibility complex (MHC). The antigensthat are recognized by the tumor specific T lymphocytes, that is, theepitopes thereof, can be molecules derived from all protein classes,such as enzymes, receptors, transcription factors, etc. which areexpressed and, as compared to unaltered cells of the same origin,usually up-regulated in cells of the respective tumor.

There are two classes of MHC-molecules, MHC class I and MHC class II.MHC class I molecules are composed of an alpha heavy chain andbeta-2-microglobulin, MHC class II molecules of an alpha and a betachain. Their three-dimensional conformation results in a binding groove,which is used for non-covalent interaction with peptides.

MHC class I molecules can be found on most nucleated cells. They presentpeptides that result from proteolytic cleavage of predominantlyendogenous proteins, defective ribosomal products (DRIPs) and largerpeptides. However, peptides derived from endosomal compartments orexogenous sources are also frequently found on MHC class I molecules.This non-classical way of class I presentation is referred to ascross-presentation in the literature (Brossart and Bevan, 1997; Rock etal., 1990). MHC class II molecules can be found predominantly onprofessional antigen presenting cells (APCs), and primarily presentpeptides of exogenous or transmembrane proteins that are taken up byAPCs e.g. during endocytosis, and are subsequently processed.

Complexes of peptide and MHC class I are recognized by CD8-positive Tcells bearing the appropriate T-cell receptor (TCR), whereas complexesof peptide and MHC class II molecules are recognized byCD4-positive-helper-T cells bearing the appropriate TCR. It is wellknown that the TCR, the peptide and the MHC are thereby present in astoichiometric amount of 1:1:1.

CD4-positive helper T cells play an important role in inducing andsustaining effective responses by CD8-positive cytotoxic T cells. Theidentification of CD4-positive T-cell epitopes derived from tumorassociated antigens (TAA) is of great importance for the development ofpharmaceutical products for triggering anti-tumor immune responses(Gnjatic et al., 2003). At the tumor site, T helper cells, support acytotoxic T cell- (CTL-) friendly cytokine milieu (Mortara et al., 2006)and attract effector cells, e.g. CTLs, natural killer (NK) cells,macrophages, and granulocytes (Hwang et al., 2007).

In the absence of inflammation, expression of MHC class II molecules ismainly restricted to cells of the immune system, especially professionalantigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells,macrophages, dendritic cells. In cancer patients, cells of the tumorhave been found to express MHC class II molecules (Dengjel et al.,2006).

Elongated (longer) peptides of the invention can act as MHC class IIactive epitopes. T-helper cells, activated by MHC class II epitopes,play an important role in orchestrating the effector function of CTLs inanti-tumor immunity. T-helper cell epitopes that trigger a T-helper cellresponse of the TH1 type support effector functions of CD8-positivekiller T cells, which include cytotoxic functions directed against tumorcells displaying tumor-associated peptide/MHC complexes on their cellsurfaces. In this way tumor-associated T-helper cell peptide epitopes,alone or in combination with other tumor-associated peptides, can serveas active pharmaceutical ingredients of vaccine compositions thatstimulate anti-tumor immune responses.

It was shown in mammalian animal models, e.g., mice, that even in theabsence of CD8-positive T lymphocytes, CD4-positive T cells aresufficient for inhibiting manifestation of tumors via inhibition ofangiogenesis by secretion of interferon-gamma (IFNγ) (Beatty andPaterson, 2001; Mumberg et al., 1999). There is evidence for CD4 T cellsas direct anti-tumor effectors (Braumuller et al., 2013; Tran et al.,2014).

Since the constitutive expression of HLA class II molecules is usuallylimited to immune cells, the possibility of isolating class II peptidesdirectly from primary tumors was previously not considered possible.However, Dengiel et al. were successful in identifying a number of MHCClass II epitopes directly from tumors (WO 2007/028574, EP 1 760 088B1).

Since both types of response, CD8 and CD4 dependent, contribute jointlyand synergistically to the anti-tumor effect, the identification andcharacterization of tumor-associated antigens recognized by either CD8+T cells (ligand: MHC class I molecule+peptide epitope) or byCD4-positive T-helper cells (ligand: MHC class II molecule+peptideepitope) is important in the development of tumor vaccines.

For an MHC class I peptide to trigger (elicit) a cellular immuneresponse, it also must bind to an MHC-molecule. This process isdependent on the allele of the MHC-molecule and specific polymorphismsof the amino acid sequence of the peptide. MHC-class-I-binding peptidesare usually 8-12 amino acid residues in length and usually contain twoconserved residues (“anchors”) in their sequence that interact with thecorresponding binding groove of the MHC-molecule. In this way each MHCallele has a “binding motif” determining which peptides can bindspecifically to the binding groove.

In the MHC class I dependent immune reaction, peptides not only have tobe able to bind to certain MHC class I molecules expressed by tumorcells, they subsequently also have to be recognized by T cells bearingspecific T cell receptors (TCR).

For proteins to be recognized by T-lymphocytes as tumor-specific or-associated antigens, and to be used in a therapy, particularprerequisites must be fulfilled. The antigen should be expressed mainlyby tumor cells and not, or in comparably small amounts, by normalhealthy tissues. In a preferred embodiment, the peptide should beover-presented by tumor cells as compared to normal healthy tissues. Itis furthermore desirable that the respective antigen is not only presentin a type of tumor, but also in high concentrations (i.e. copy numbersof the respective peptide per cell). Tumor-specific and tumor-associatedantigens are often derived from proteins directly involved intransformation of a normal cell to a tumor cell due to their function,e.g. in cell cycle control or suppression of apoptosis. Additionally,downstream targets of the proteins directly causative for atransformation may be up-regulated und thus may be indirectlytumor-associated. Such indirect tumor-associated antigens may also betargets of a vaccination approach (Singh-Jasuja et al., 2004). It isessential that epitopes are present in the amino acid sequence of theantigen, in order to ensure that such a peptide (“immunogenic peptide”),being derived from a tumor associated antigen, leads to an in vitro orin vivo T-cell-response.

Basically, any peptide able to bind an MHC molecule may function as aT-cell epitope. A prerequisite for the induction of an in vitro or invivo T-cell-response is the presence of a T cell having a correspondingTCR and the absence of immunological tolerance for this particularepitope.

Therefore, TAAs are a starting point for the development of a T cellbased therapy including but not limited to tumor vaccines. The methodsfor identifying and characterizing the TAAs are usually based on the useof T-cells that can be isolated from patients or healthy subjects, orthey are based on the generation of differential transcription profilesor differential peptide expression patterns between tumors and normaltissues. However, the identification of genes over-expressed in tumortissues or human tumor cell lines, or selectively expressed in suchtissues or cell lines, does not provide precise information as to theuse of the antigens being transcribed from these genes in an immunetherapy. This is because only an individual subpopulation of epitopes ofthese antigens are suitable for such an application since a T cell witha corresponding TCR has to be present and the immunological tolerancefor this particular epitope needs to be absent or minimal. In a verypreferred embodiment of the invention it is therefore important toselect only those over- or selectively presented peptides against whicha functional and/or a proliferating T cell can be found. Such afunctional T cell is defined as a T cell, which upon stimulation with aspecific antigen can be clonally expanded and is able to executeeffector functions (“effector T cell”).

In case of targeting peptide-MHC by specific TCRs (e.g. soluble TCRs)and antibodies or other binding molecules (scaffolds) according to theinvention, the immunogenicity of the underlying peptides is secondary.In these cases, the presentation is the determining factor.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, the present inventionrelates to a peptide comprising an amino acid sequence selected from thegroup consisting of SEQ ID NO: 1 to SEQ ID NO: 640 or a variant sequencethereof which is at least 77%, preferably at least 88%, homologous(preferably at least 77% or at least 88% identical) to SEQ ID NO: 1 toSEQ ID NO: 640, wherein said variant binds to MHC and/or induces T cellscross-reacting with said peptide, or a pharmaceutical acceptable saltthereof, wherein said peptide is not the underlying full-lengthpolypeptide.

The present invention further relates to a peptide of the presentinvention comprising a sequence that is selected from the groupconsisting of SEQ ID NO: 1 to SEQ ID NO: 640 or a variant thereof, whichis at least 77%, preferably at least 88%, homologous (preferably atleast 77% or at least 88% identical) to SEQ ID NO: 1 to SEQ ID NO: 640,wherein said peptide or variant thereof has an overall length of between8 and 100, preferably between 8 and 30, and most preferred of between 8and 14 amino acids.

The following tables show the peptides according to the presentinvention, their respective SEQ ID NOs, and the prospective source(underlying) genes for these peptides. All peptides in Table 1 and Table2 bind to HLA-A*02. The peptides in Table 2 have been disclosed beforein large listings as results of high-throughput screenings with higherror rates or calculated using algorithms, but have not been associatedwith cancer at all before. The peptides in Table 3 are additionalpeptides that may be useful in combination with the other peptides ofthe invention. The peptides in Table 4 are furthermore useful in thediagnosis and/or treatment of various other malignancies that involve anover-expression or over-presentation of the respective underlyingpolypeptide.

TABLE 1 Peptides according to the present invention. J = phospho-serine.SEQ ID NO. Sequence Gene ID(s) Official Gene Symbol(s) 1 SLMEPPAVLLL8900 CCNA1 2 SLLEADPFL 8900 CCNA1 3 SLASKLTTL 94025 MUC16 4 GIMEHITKI94025 MUC16 5 HLTEVYPEL 94025 MUC16 6 VLVSDGVHSV 1952 CELSR2 7 SLVGLLLYL100101267, 9883 POM121C, POM121 8 FTLGNVVGMYL 100287425, 647087 C7orf739 GAAKDLPGV 100534599, 57461 ISY1-RAB43, ISY1 10 FLATFPLAAV 10076 PTPRU11 KIFEMLEGV 101060208, 101060210, CT45A3, CT45A4, 101060211, 441519,CT45A5, CT45A6, 441520, 441521, 541465, CT45A1, CT45A2 541466, 728911 12SLWPDPMEV 101060557, 146177 VWA3A 13 YLMDESLNL 101060756, 115948 CCDC15114 AAYGGLNEKSFV 10140 TOB1 15 VLLTFKIFL 10149 GPR64 16 VLFQGQASL 10154PLXNC1 17 GLLPGDRLVSV 10207 INADL 18 YLVAKLVEV 10277 UBE4B 19FMVDNEAIYDI 10376, 112714, 113457, TUBA1B, TUBA3E,51807, 7277, 7278, 7846, TUBA3D, TUBA8, 84790 TUBA4A, TUBA3C,TUBA1A, TUBA1C 20 RMIEYFIDV 10396, 153020 ATP8A1, RASGEF1B 21 VLDELDMEL10437 IFI30 22 IMEENPGIFAV 10558 SPTLC1 23 VLLDDIFAQL 10565 ARFGEF1 24SLSDGLEEV 10651 MTX2 25 FLPDEPYIKV 10686 CLDN16 26 ALLELAEEL10694, 644131 CCT8, CCT8P1 27 ILADIVISA 10797 MTHFD2 28 QLLDETSAITL10915 TCERG1 29 KMLGIPISNILMV 10964 IFI44L 30 LILDWVPYI 10975 UQCR11 31YLAPELFVNV 11035 RIPK3 32 KLDDLTQDLTV 11116 FGFR1OP 33 VLLSLLEKV 1130LYST 34 ILVEADSLWVV 11329 STK38 35 KINDTIYEV 113510 HELQ 36 YVLEDLEVTV114960, 22820, 26958 TSGA13, COPG1, COPG2 37 LLWDVVTGQSV 114987 WDR31 38FLLEDDIHVS 116461 TSEN15 39 SVAPNLPAV 120114 FAT3 40 TLLVKVFSV 122402TDRD9 41 SLMPHIPGL 122402 TDRD9 42 VLLQKIVSA 122402 TDRD9 43 VLSSLEINI1233 CCR4 44 ILDPISSGFLL 127795 C1orf87 45 SLWQDIPDV 128272 ARHGEF19 46ILTEENIHL 130540 ALS2CR12 47 ILLSVPLLVV 1314 COPA 48 ALAELYEDEV 137886UBXN2B 49 YLPAVFEEV 9961 MVP 50 SLSELEALM 143686 SESN3 51 LLPDLEFYV143888 KDELC2 52 FLLAHGLGFLL 144110 TMEM86A 53 KMIETDILQKV 146562C16orf71 54 SLLEQGKEPWMV 147949, 163087, 342892, ZNF583, ZNF383,374899, 84503 ZNF850, ZNF829, ZNF527 55 SLLDLETLSL 148137 C19orf55 56KLYEGIPVLL 152110 NEK10 57 TLAELQPPVQL 157922 CAMSAP1 58 FLDTLKDLI 162AP1B1 59 IMEDIILTL 1656 DDX6 60 SLTIDGIYYV 1659 DHX8 61 FLQGYQLHL 19ABCA1 62 VLLDVSAGQLLM 196463 PLBD2 63 YLLPSGGSVTL196483, 286042, 348926, FAM86A, FAM86B3P, 55199, 692099FAM86EP, FAM86C1, FAM86DP 64 YAAPGGLIGV 1968, 255308 EIF2S3 65LKVNQGLESL 197358 NLRC3 66 FLDENIGGVAV 200424 TET3 67 TLLAEALVTV 200958MUC20 68 SLMELPRGLFL 219527 LRRC55 69 FQLDPSSGVLVTV 2196 FAT2 70GLLDYPVGV 219736 STOX1 71 GILARIASV 221322 C6orf170 72 SLLELDGINL 221806VWDE 73 NIFDLQIYV 222256 CDHR3 74 ALLDPEVLSIFV 22898 DENND3 75 GLLEVMVNL23001 WDFY3 76 ILIDSIYKV 23007 PLCH1 77 ILVEADGAWVV 23012 STK38L 78SLFSSLEPQIQPV 23029 RBM34 79 SLFIGEKAVLL 23029 RBM34 80 FLYDNLVESL 23132RAD54L2 81 FLFSQLQYL 23165 NUP205 82 FLSSVTYNL 23312 DMXL2 83 ILAPTVMMI23312 DMXL2 84 VTFGEKLLGV 23428 SLC7A8 85 KMSELRVTL 23499 MACF1 86NLIGKIENV 23639 LRRC6 87 ALPEAPAPLLPHIT 23786 BCL2L13 88 FLLVGDLMAV23787 MTCH1 89 YILPTETIYV 254956 MORN5 90 TLLQIIETV 256309 CCDC110 91IMQDFPAEIFL 25914 RTTN 92 YLIPFTGIVGL 26001 RNF167 93 LLQAIKLYL 260293CYP4X1 94 YLIDIKTIAI 26160 IFT172 95 SVIPQIQKV 26272 FBXO4 96 YIFTDNPAAV26301 GBGT1 97 SLINGSFLV 27 ABL2 98 LIIDQADIYL 27042 DIEXF 99 ALVSKGLATV27044 SND1 100 YLLSTNAQL 27285 TEKT2 101 ILVGGGALATV 2820 GPD2 102YLFESEGLVL 283431 GAS2L3 103 TLAEEVVAL 283755, 400322, 8924HERC2P3, HERC2P2, HERC2 104 STMEQNFLL 284110 GSDMA 105 LLLEHSFEI 284361EMC10 106 LLYDAVHIVSV 2899 GRIK3 107 FLQPVDDTQHL 2906 GRIN2D 108ALFPGVALLLA 2923 PDIA3 109 IILSILEQA 2953, 653689 GSTT2, GSTT2B 110FLSQVDFEL 2968 GTF2H4 111 YVWGFYPAEV 3109 HLA-DMB 112 FLITSNNQL353497, 79441 POLN, HAUS3 113 GLLPTPLFGV 359710 BPIFB3 114 SLVGEPILQNV359710 BPIFB3 115 AIAGAGILYGV 362 AQP5 116 YHIDEEVGF 3620 IDO1 117ILPDGEDFLAV 3636 INPPL1 118 KLIDNNINV 3696 ITGB8 119 FLYIGDIVSL 3709ITPR2 120 ALLGIPLTLV 3777, 60598 KCNK3, KCNK15 121 GVVDPRAISVL387522, 7335 TMEM189-UBE2V1, UBE2V1 122 FLLAEDDIYL 389677 RBM12B 123NLWDLTDASVV 3959 LGALS3BP 124 ALYETELADA 4001 LMNB1 125 VQIHQVAQV 4053LTBP2 126 VLAYFLPEA 4171 MCM2 127 KIGDEPPKV 4291 MLF1 128 YLFDDPLSAV4363 ABCC1 129 GLLDGGVDILL 4548 MTR 130 FLWNGEDSALL 4586, 727897MUC5AC, MUC5B 131 FVPPVTVFPSL 4586, 727897 MUC5AC, MUC5B 132 LLVEQPPLAGV4773 NFATC2 133 KVLSNIHTV 4867 NPHP1 134 YLQELIFSV 51000 SLC35B3 135ALSEVDFQL 51059 FAM135B 136 YLADPSNLFVV 51072, 728556 MEMO1, MEMO1P1 137TLVLTLPTV 51073 MRPL4 138 YQYPRAILSV 51105 PHF20L1 139 SVMEVNSGIYRV51182 HSPA14 140 YMDAPKAAL 51246 SHISA5 141 YLDFSNNRL 51284 TLR7 142FLFATPVFI 51296 SLC15A3 143 LLLDITPEI 51430 SUCO 144 YIMEPSIFNTL 51497TH1L 145 FLATSGTLAGI 51522 TMEM14C 146 SLATAGDGLIEL 5245 PHB 147SLLEAVSFL 5261 PHKG2 148 ALNPEIVSV 5277 PIGA 149 NLLELFVQL 5297 PI4KA150 RLWEEGEELEL 5329 PLAUR 151 KILQQLVTL 541468 LURAP1 152 ILFEDIFDV5437 POLR2H 153 FLIANVLYL 5476 CTSA 154 ALDDGTPAL 54798 DCHS2 155RVANLHFPSV 54809 SAMD9 156 AISQGITLPSL 54856 GON4L 157 SLNDEVPEV 54919HEATR2 158 KLFDVDEDGYI 54947 LPCAT2 159 GLVGNPLPSV 55127 HEATR1 160FLFDEEIEQI 55132 LARP1B 161 ALLEGVNTV 55211 DPPA4 162 YQQAQVPSV 55217TMLHE 163 ALDEMGDLLQL 55304 SPTLC3 164 ALLPQPKNLTV 5546 PRCC 165SLLDEIRAV 55567 DNAH3 166 YLNHLEPPV 55666 NPLOC4 167 KVLEVTEEFGV 55705IPO9 168 KILDADIQL 55779 WDR52 169 NLPEYLPFV 55832, 91689CAND1, C22orf32 170 RLQETLSAA 5591 PRKDC 171 LLLPLQILL 5650 KLK7 172VLYSYTIITV 56941 C3orf37 173 LLDSASAGLYL 56992 KIF15 174 ALAQYLITA 57060PCBP4 175 YLFENISQL 57115 PGLYRP4 176 YLMEGSYNKVFL 5714 PSMD8 177YLLPEEYTSTL 57143 ADCK1 178 ALTEIAFVV 57148 RALGAPB 179 KVLNELYTV 57522SRGAP1 180 FQIDPHSGLVTV 57526 PCDH19 181 LLWAGTAFQV 57535 KIAA1324 182MLLEAPGIFL 57570 TRMT5 183 FGLDLVTEL 57674 RNF213 184 YLMDINGKMWL 57674RNF213 185 FLIDDKGYTL 57685 CACHD1 186 TLFFQQNAL 5771 PTPN2 187RQISIRGIVGV 5836 PYGL 188 GLFPVTPEAV 59352 LGR6 189 ALQRKLPYV 60598KCNK15 190 FLSSLTETI 629 CFB 191 LLQEGQALEYV 629 CFB 192 KMLDGASFTL63941 NECAB3 193 QLLDADGFLNV 63967 CLSPN 194 ALPLFVITV 64078 SLC28A3 195GLFADLLPRL 642475 MROH6 196 YLYSVEIKL 642987 TMEM232 197 ALGPEGGRV 64321SOX17 198 KTINKVPTV 6498 SKIL 199 ALQDVPLSSV 65003 MRPL11 200 LLFGSVQEV65250 C5orf42 201 RLVDYLEGI 65260 SELRC1 202 ALLDQQGSRWTL 6565 SLC15A2203 VLLEDAHSHTL 6614 SIGLEC1 204 KIAENVEEV 6804 STX1A 205 SLYPGTETMGL6840 SVIL 206 VLQEGKLQKLAQL 6891 TAP2 207 GLTSTNAEV 7029 TFDP2 208KISPVTFSV 728661, 9906 SLC35E2B, SLC35E2 209 KLIESKHEV 7328 UBE2H 210LLLNAVLTV 7374 UNG 211 LLWPGAALL 7462 LAT2 212 ALWDQDNLSV 7464 CORO2A213 VTAAYMDTVSL 7498 XDH 214 FLLDLDPLLL 7915 ALDH5A1 215 QLINHLHAV 79365BHLHE41 216 NLWEDPYYL 79659 DYNC2H1 217 ALIHPVSTV 79690 GAL3ST4 218SALEELVNV 79707 NOL9 219 KLSDIGITV 79725 THAP9 220 LLQKFVPEI 79832 QSER1221 ALYEEGLLL 80311 KLHL15 222 NLIENVQRL 8195 MKKS 223 ALLENIALYL 833CARS 224 TLIDAQWVL 84000 TMPRSS13 225 SLLKVLPAL 84125 LRRIQ1 226MLYVVPIYL 84187 TMEM164 227 ALMNTLLYL 84197 228 AMQEYIAVV 84320 ACBD6229 RLPGPLGTV 84875 PARP10 230 ILVDWLVEV 85417, 890, 8900 CCNB3, CCNA2,CCNA1 231 FLSPQQPPLLL 8621 CDK13 232 ALLEAQDVELYL 8701 DNAH11 233VLSETLYEL 8914 TIMELESS 234 ALMEDTGRQML 89782 LMLN 235 YLNDLHEVLL 898CCNE1 236 GLLEAKVSL 89845 ABCC10 237 ALLEASGTLLL 90580 C19orf52 238YLISFQTHI 90592 ZNF700 239 AAFAGKLLSV 91543 RSAD2 240 ILLEQAFYL 92255LMBRD2 241 SLVEVNPAYSV 92305 TMEM129 242 AIAYILQGV 92335 STRADA 243LLLNELPSV 92345 NAF1 244 SLFGGTEITI 93035 PKHD1L1 245 SMIDDLLGV 93233CCDC114 246 LLWEVVSQL 9462 RASAL2 247 VLLPNDLLEKV 9472 AKAP6 248FLFPNQYVDV 9632 SEC24C 249 LLDGFLVNV 9632 SEC24C 250 ALSEEGLLVYL 9690UBE3C 251 ALYTGFSILV 972 CD74 252 LLIGTDVSL 9730 VPRBP 253 GLDAATATV9869 SETDB1 254 TLLAFIMEL 987 LRBA 255 VLASYNLTV 987 LRBA 256FLPPEHTIVYI 9896 FIG4 257 SIFSAFLSV 9918 NCAPD2 258 ELAERVPAI 9918NCAPD2 259 TLMRQLQQV 140680 C20orf96 260 TLLEGPDPAELLL 100101267, 9883POM121C, POM121 261 YVLEFLEEI 10026 PIGK 262 LLWGDLIWL101060729, 548593, 79008 SLX1A, SLX1B 263 LLVSNLDFGV 10189 ALYREF 264SLQEQLHSV 133584 EGFLAM 265 LLFGGTKTV 1572 CYP2F1 266 KITDTLIHL 2099ESR1 267 ALQDFLLSV 2189 FANCG 268 IAGPGLPDL 220074 LRTOMT 269RVLEVGALQAV 25885 POLR1A 270 LLLDEEGTFSL 27013 CNPPD1 271 LVYPLELYPA29956 CERS2 272 ALGNTVPAV 352909 DNAAF3 273 NLFQSVREV 367 AR 274SLLFSLFEA 3938 LCT 275 YLVYILNEL 51202 DDX47 276 ALFTFSPLTV 54665 RSBN1277 LLPPLESLATV 5518 PPP2R1A 278 QLLDVVLTI 55295 KLHL26 279 ALWGGTQPLL56063 TMEM234 280 VLPDPEVLEAV 57326 PBXIP1 281 ILRESTEEL 57639 CCDC146282 LLADVVPTT 57661 PHRF1 283 ALYIGDGYVIHLA 5920 RARRES3 284 ILLSQTTGV7175 TPR 285 QLLHVGVTV 79598 CEP97 286 YLFPGIPEL 80308 FLAD1 287FLNEFFLNV 833 CARS 288 NLINEINGV 8672 EIF4G3 289 VLLEIEDLQV 8826 IQGAP1290 GLLDLNNAILQL 2104 ESRRG 291 GLDSNLKYILV 23269 MGA 292 LLWEAGSEA26167 PCDHB5 293 GLGELQELYL 2811 GP1BA 294 ILDPFQYQL 9420 CYP7B1 295VLDRESPNV 1000 CDH2 296 FMEGAIIYV 10006 ABI1 297 VLADIELAQA 10039 PARP3298 VMITKLVEV 10076 PTPRU 299 YLLETSGNL 10135 NAMPT 300 ALLGQTFSL 10147SUGP2 301 FLVEDLVDSL 10313, 6253 RTN3, RTN2 302 ALLQEGEVYSA 10594 PRPF8303 AILPQLFMV 10945 KDELR1 304 MTLGQIYYL 10959 TMED2 305 SIANFSEFYV111, 112 ADCY5, ADCY6 306 ALVNVQIPL 11194 ABCB8 307 ALPVSLPQI 11218DDX20 308 SQYSGQLHEV 114884 OSBPL10 309 GLFDGVPTTA 122618 PLD4 310FLVDTPLARA 124975 GGT6 311 RLYTGMHTV 130367 SGPP2 312 IISDLTIAL 144110TMEM86A 313 VLFDDELLMV 1687 DFNA5 314 ALIAEGIALV 1778 DYNC1H1 315YLQDVVEQA 19 ABCA1 316 ILLERLWYV 215 ABCD1 317 SLAALVVHV 2196 FAT2 318GLINTGVLSV 221656 KDM1B 319 SLEPQIQPV 23029 RBM34 320 KMFEFVEPLL 23092ARHGAP26 321 GLFEDVTQPGILL 23140 ZZEF1 322 TLMTSLPAL 23154 NCDN 323IQIGEETVITV 2316 FLNA 324 FLYDEIEAEV 23191, 26999 CYFIP1, CYFIP2 325FIMPATVADATAV 23352 UBR4 326 FLPEALDFV 23511 NUP188 327 GLAPFTEGISFV23780 APOL2 328 ALNDQVFEI 2475 MTOR 329 FLVTLNNVEV 25839 COG4 330QLALKVEGV 25896 INTS7 331 KVDTVWVNV 25917 THUMPD3 332 YLISELEAA 25940FAM98A 333 FLPDANSSV 25942 SIN3A 334 TLTKVLVAL 26292 MYCBP 335 YSLSSVVTV28396, 3500, 3501, 3502, IGHV4-31, IGHG1, 3503, 3507IGHG2, IGHG3, IGHG4, IGHM 336 ILLTAIVQV 29100 TMEM208 337 HLLSELEAAPYL2976 GTF3C2 338 SVLEDPVHAV 29927 SEC61A1 339 GLWEIENNPTVKA 3068 HDGF 340ALLSMTFPL 3094 HINT1 341 SQIALNEKLVNL 339799, 8665 EIF3FP3, EIF3F 342HIYDKVMTV 340706 VWA2 343 SLLEVNEESTV 3428 IFI16 344 YLQDQHLLLTV 3636INPPL1 345 VIWKALIHL 3689 ITGB2 346 LLDSKVPSV 3691 ITGB4 347SLFKHDPAAWEA 3728 JUP 348 ILLDVKTRL 3728, 3861, 3868, 3872JUP, KRT14, KRT16, KRT17 349 SLTEYLQNV 3799 KIF5B 350 ALLDVTHSELTV 3911LAMA5 351 SLIPNLRNV 3949 LDLR 352 SLLELLHIYV 401494 PTPLAD2 353YLFEMDSSL 4074 M6PR 354 LILEGVDTV 4126 MANBA 355 SIQQSIERLLV 4809 NHP2L1356 KLLGKLPEL 4929 NR4A2 357 SMHDLVLQV 51435 SCARA3 358 ALDEYTSEL 51477ISYNA1 359 YLLPESVDL 51657 STYXL1 360 ALDJGASLLHL 54101 RIPK4 361ALYELEGTTV 54625 PARP14 362 TLYGLSVLL 54896 PQLC2 363 KVLDVSDLESV 54961SSH3 364 LLQNEQFEL 55329 MNS1 365 YVIDQGETDVYV 5573 PRKAR1A 366RLLDMGETDLML 55898 UNC45A 367 SLQNHNHQL 56254, 9810 RNF20, RNF40 368ILLEEVSPEL 5660 PSAP 369 GLFPEHLIDV 56997 ADCK3 370 SLLQDLVSV 57169ZNFX1 371 FLQAHLHTA 57674 RNF213 372 TMLLNIPLV 57674 RNF213 373SLLEDKGLAEV 59342 SCPEP1 374 FLLQQHLISA 5993 RFX5 375 SLTETIEGV 629 CFB376 AMFESSQNVLL 64328 XPO4 377 FLLDSSASV 64856 VWA1 378 ALGYFVPYV 6567SLC16A2 379 IMEGTLTRV 6654 SOS1 380 TLIEDEIATI 6788 STK3 381 FIDEAYVEV6873 TAF2 382 ALQNYIKEA 7022 TFAP2C 383 ALLELENSVTL 715, 83481C1R, EPPK1 384 ILFANPNIFV 728689, 8663 EIF3CL, EIF3C 385 SLLEQGLVEA 7468WHSC1 386 ILFRYPLTI 767 CA8 387 ALFQATAEV 7840 ALMS1 388 SLTIDGIRYV79665 DHX40 389 LLADVTHLL 79699 ZYG11B 390 ALFMKQIYL 79781 IQCA1 391YVYPQRLNFV 81704 DOCK8 392 ALLHPQGFEV 8269 TMEM187 393 GLLDTQTSQVLTA83481 EPPK1 394 LLAVIGGLVYL 84061 MAGT1 395 ALALGGIAVV 84159 ARID5B 396ALLPDLPAL 84273 NOA1 397 YLFGERLLEC 84365 MKI67IP 398 KLLEEDGTIITL 84612PARD6B 399 YLFEPLYHV 8534 CHST1 400 SLLTEQDLWTV 90806 ANGEL2 401ILLDDTGLAYI 9125 RQCD1 402 VLFSGALLGL 968 CD68 403 KLYDRILRV 9746 CLSTN3404 AIDIJGRDPAV 100288805, 54768 HYDIN2, HYDIN 405 ALYDVFLEV 1774DNASE1L1 406 SVQGEDLYLV 2880 GPX5 407 YLMDLINFL 54536 EXOC6 408VLDDSIYLV 57565 KLHL14 409 LLDAMNYHL 57565 KLHL14 410 VLSDVIPJI 139231FAM199X 411 LLAHLSPEL 57194 ATP10A 412 YLDDLNEGVYI 9897 KIAA0196 413TLLEKVEGC 149371 EXOC8 414 YVDDIFLRV 19 ABCA1 415 LLDKVYSSV221960, 51622 CCZ1B, CCZ1 416 VLSDIIQNLSV 3071 NCKAP1L 417 NLQDTEYNL 472ATM 418 ALAELENIEV 55561 CDC42BPG 419 GQYEGKVSSV 55705 IPO9 420FMYDTPQEV 629 CFB 421 RLPETLPSL 6337 SCNN1A 422 FLPKLLLLA 6614 SIGLEC1423 GLDGPPPTV 7127 TNFAIP2 424 TLLDALYEI 8690 JRKL 425 FLYEKSSQV 89876MAATS1 426 RLADKSVLV 9918 NCAPD2

TABLE 2 Additional peptides according to the present invention with noprior known cancer association. J = phospho-serine. SEQ ID NO. SequenceGene ID(s) Official Gene Symbol(s) 427 ALLPLSPYL 79679 VTCN1 428KLGHTDILVGV 23016 EXOSC7 429 GLVNDLARV 10075 HUWE1 430 HLYSSIEHLTT 10075HUWE1 431 SLVNVVPKL 1020 CDK5 432 TLIEESAKV 10257 ABCC4 433 AMLNEPWAV10379, 55072 IRF9, RNF31 434 KVSNSGITRV 10575 CCT4 435 WLMPVIPAL10809, 134266, STARD10, GRPEL2, FBXW8, 26259, 30820,KCNIP1, FAM208B, C8orf44, 54906, 56260, ISY1, SHROOM3, SLC25A14,57461, 57619, L3MBTL4, C12orf65 9016, 91133, 91574 436 HLAEVSAEV 11130ZWINT 437 SMAPGLVIQAV 11160 ERLIN2 438 KLLPLAGLYL 113655 MFSD3 439YLLQEIYGI 114804, 23295 RNF157, MGRN1 440 ALADGVTMQV 114960, 26958TSGA13, COPG2 441 ALLENPKMEL 140901, 149420 STK35, PDIK1L 442GLLGGGGVLGV 149954 BPIFB4 443 GLWEIENNPTV 154150, 3068 HDGFL1, HDGF 444GLLRDEALAEV 1663, 440081, DDX11, DDX12P 642846 445 GLYQDPVTL 201292TRIM65 446 QLIPALAKV 2070, 2138, 2139 EYA4, EYA1, EYA2 447 QLVPALAKV2140 EYA3 448 NLLETKLQL 219988 PATL1 449 KLAEGLDIQL 221656 KDM1B 450FMIDASVHPTL 221960, 51622 CCZ1B, CCZ1 451 LLLLDTVTMQV 22820 COPG1 452ILLEHGADPNL 22852 ANKRD26 453 KLLEATSAV 100129478, C4orf46 201725 454KLPPPPPQA 23028 KDM1A 455 SLLKEPQKVQL 23154 NCDN 456 LLIGHLERV 23165NUP205 457 SLLPGNLVEKV 23341 DNAJC16 458 SLIDKLYNI 25885 POLR1A 459ALITEVVRL 26005 C2CD3 460 AMLEKNYKL 26160 IFT172 461 VMFRTPLASV 26271FBXO5 462 KLAKQPETV 27085 MTBP 463 SLVESHLSDQLTL 284361 EMC10 464ALNDCIYSV 3652 IPP 465 QLCDLNAEL 3833 KIFC1 466 VLIANLEKL 440590 ZYG11A467 FLAKDFNFL 4600 MX2 468 YLRSVGDGETV 4904, 8531 YBX1, CSDA 469YLASDEITTV 4976 OPA1 470 MLQDSIHVV 4999 ORC2 471 YLYNNMIAKI 51284 TLR7472 KLLEVSDDPQV 51606 ATP6V1H 473 AMATESILHFA 5297 PI4KA 474YLDPALELGPRNV 537 ATP6AP1 475 LLLNEEALAQI 54497 HEATR5B 476 ALMERTGYSMV54502 RBM47 477 ALLPASGQIAL 54512 EXOSC4 478 YLLHEKLNL 55010 PARPBP 479SLFGNSGILENV 55125 CEP192 480 ALLEDSCHYL 55161 TMEM33 481 GLIEDYEALL55755 CDK5RAP2 482 SLAPAGIADA 55839 CENPN 483 ALTDIVSQV 56924 PAK6 484SLIEKVTQL 56992 KIF15 485 NVPDSFNEV 57508 INTS2 486 AVMESIQGV 57646USP28 487 LLINSVFHV 57655 GRAMD1A 488 FLAEDPKVTL 60489 APOBEC3G 489KMWEELPEVV 622 BDH1 490 FLLQHVQEL 64127 NOD2 491 GLNDRSDAV 64151 NCAPG492 SLFDGFADGLGV 64219, 9867 PJA1, PJA2 493 GLLGEKTQDLIGV 6522 SLC4A2494 ALQPEPIKV 6653 SORL1 495 FIFSEKPVFV 6653 SORL1 496 FLVEKQPPQV 6778STAT6 497 GLLEKLTAI 6875 TAF4B 498 KLWTGGLDNTV 7088, 7090, 7091TLE1, TLE3, TLE4 499 KIFDIDEAEEGV 728350, 8894 EIF2S2P4, EIF2S2 500SLMEDQVLQL 7486 WRN 501 LLDPNVKSIFV 79033 ERI3 502 RLLAQVPGL 79096C11orf49 503 SLNHFTHSV 79670 ZCCHC6 504 GLSDGNPSL 79684 MSANTD2 505SLAPGDVVRQV 79729 SH3D21 506 KLLGKVETA 80185 TTI2 507 KLIDDQDISISL 80208SPG11 508 ILAQEQLVVGV 80347 COASY 509 FLFDTKPLIV 821 CANX 510 KLYSVVSQL8239, 8287 USP9X, USP9Y 511 FLDPYCSASV 85415 RHPN2 512 SLSEIVPCL 8900CCNA1 513 SLWPSPEQL 90480 GADD45GIP1 514 ILVDWLVQV 9133 CCNB2 515LLQELVLFL 93589 CACNA2D4 516 AVGPASILKEV 9406 ZRANB2 517 LLMPIPEGLTL9540 TP5313 518 KLNAEVACV 9569 GTF2IRD1 519 GLLHLTLLL 9603 NFE2L3 520LAVHPSGVAL 9636 ISG15 521 MLLTKLPTI 9804 TOMM20 522 TLWYRSPEV 983 CDK1523 YQIPRTFTL 9846 GAB2 524 ALIENLTHQI 100508782, 9677 PPIP5K1 525VLLEAGEGLVTI 10072, 582 DPP3, BBS1 526 RLAEVGQYEQV 23019 CNOT1 527FLLEPGNLEV 23218 NBEAL2 528 SVAEGRALMSV 51428 DDX41 529 LLADELITV 56904SH3GLB2 530 VMYADIGGMDI 5704 PSMC4 531 YTLPIASSIRL 7249 TSC2 532ALNNLLHSL 101060416, SMG1, BOLA2, SMG1P1 101060589, 23049,440345, 440354, 552900, 641298 533 RMVAEIQNV 11262 SP140 534 HLANIVERL117854, 445372, TRIM6, TRIM6-TRIM34, 53840 TRIM34 535 KLIAQNLEL 3832KIF11 536 YLVEGRFSV 55125 CEP192 537 TLAPGEVLRSV 3996 LLGL1 538LLLAHIIAL 9415 FADS2 539 ALFDAQAQV 7297 TYK2 540 ALIPETTTLTV100529251, 51192 CKLF-CMTM1, CKLF 541 SMLEPVPEL 10277 UBE4B 542RVWDISTVSSV 11137 PWP1 543 GLLPTPITQQASL 133619 PRRC1 544 LLWDVPAPSL1388, 7148 ATF6B, TNXB 545 LLADLLHNV 1677 DFFB 546 VMIAGKVAVV 191 AHCY547 TLDITPHTV 2177 FANCD2 548 ALWENPESGEL 22893 BAHD1 549 AMLENASDIKL 23ABCF1 550 FLYDEIEAEVNL 23191, 26999 CYFIP1, CYFIP2 551 KLYESLLPFA 23310NCAPD3 552 GLLDLPFRVGV 23347 SMCHD1 553 SLLNQDLHWSL 23355 VPS8 554LLMPSSEDLLL 26046 LTN1 555 YVLEGLKSV 26098 C10orf137 556 FLTDLEDLTL26151 NAT9 557 KLYDDMIRL 26160 IFT172 558 GLLENIPRV 2618 GART 559VTVPPGPSL 266971, 5710 PIPSL, PSMD4 560 ALWDIETGQQTTT 2782 GNB1 561YLQLTQSEL 283237 TTC9C 562 YLEELPEKLKL 2944, 2949 GSTM1, GSTM5 563WLLPYNGVTV 2976 GTF3C2 564 TVTNAVVTV 3312 HSPA8 565 ALQETPTSV 3434 IFIT1566 VIADGGIQNV 3615 IMPDH2 567 SLLPLDDIVRV 3708, 3709 ITPR1, ITPR2 568TLYDIAHTPGV 4191 MDH2 569 KLVDRTWTL 441733, 5613, PRKXP1, PRKX, PRKY5616 570 ALANQIPTV 4436 MSH2 571 LLLTTIPQI 4507 MTAP 572 ALADLIEKELSV4850 CNOT4 573 ILVANAIVGV 488, 489 ATP2A2, ATP2A3 574 YLLQEPPRTV 5074PAWR 575 YLISQVEGHQV 51002 TPRKB 576 ILLNNSGQIKL 51755 CDK12 577VMFEDGVLMRL 545 ATR 578 FLDPGGPMMKL 55627 SMPD4 579 NLMEMVAQL 55636 CHD7580 LLMENAERV 55726 ASUN 581 RLWNETVEL 55789 DEPDC1B 582 TLCDVILMV 55975KLHL7 583 ILANDGVLLAA 5685 PSMA4 584 ALAEVAAMENV 56987 BBX 585ALWDLAADKQTL 5701 PSMC2 586 KLKPGDLVGV 5702 PSMC3 587 VMNDRLYAI 57565KLHL14 588 SLLPLSHLV 57674 RNF213 589 KLYPQLPAEI 57724 EPG5 590SLIEKLWQT 5991 RFX3 591 SMAELDIKL 60561 RINT1 592 RLLJAAENFL 64092SAMSN1 593 GLPRFGIEMV 64397 ZFP106 594 IMLKGDNITL 6635 SNRPE 595VLLSIYPRV 6890 TAP1 596 ALLDQTKTLAESAL 7094 TLN1 597 KLLEGQVIQL 7629ZNF76 598 FLFPHSVLV 79022 TMEM106C 599 YLLNDASLISV 79145 CHCHD7 600ALAAPDIVPAL 79886 CAAP1 601 SAFPFPVTV 79939 SLC35E1 602 YLLEQIKLIEV79956 ERMP1 603 FLIEPEHVNTV 80124 VCPIP1 604 SILDRDDIFV 8237 USP11 605KLYEAVPQL 8317 CDC7 606 ALWETEVYI 8398 PLA2G6 607 RLYSGISGLEL 84172POLR1B 608 SLLSVSHAL 84219 WDR24 609 ALWKQLLEL 85441 HELZ2 610LLAPTPYIIGV 8567 MADD 611 YLLDDGTLVV 8872 CDC123 612 YLYNEGLSV 899 CCNF613 RLLPPGAVVAV 90353 CTU1 614 LLLPDQPPYHL 9246 UBE2L6 615 VLPPDTDPA93100 NAPRT1 616 VLIDEVESL 9319 TRIP13 617 ALMYESEKVGV 9342 SNAP29 618VLFDSESIGIYV 9555 H2AFY 619 ALQDRVPLA 9636 ISG15 620 KLLNKIYEA 9875 URB1621 VLMDRLPSLL 9875 URB1 622 RLLGEEVVRVLQA 9894 TELO2 623 YLVEDIQHI 9985REC8 624 FLQEEPGQLL 101060729, SLX1A, SLX1B 548593, 79008 625VVLEGASLETV 10436 EMG1 626 LLMATILHL 1315 COPB1 627 KLLETELLQEI 151636DTX3L 628 KLWEFFQVDV 178 AGL 629 HLLNESPML 23165 NUP205 630 LLSHVIVAL545 ATR 631 FLDVFLPRV 5591 PRKDC 632 YLIPDIDLKL 6599 SMARCC1 633ALSRVSVNV 80746 TSEN2 634 VVAEFVPLI 8295 TRRAP 635 SLDSTLHAV 85444LRRCC1 636 LLTEIRAVV 9263 STK17A 637 SIYGGFLLGV 9276 COPB2 638 KLIQESPTV9702 CEP57 639 SLFQNCFEL 9716 AQR 640 YLFSEALNAA 987 LRBA

TABLE 3 Peptides useful for cancer therapy,e.g. personalized cancer therapies SEQ ID Official Gene  NO. SequenceGene ID(s) Symbol(s) 641 VLLPVEVATHYL 10568 SLC34A2 642 FLHDISDVQL 10715CERS1 643 ALFPHLLQPV 1434 CSE1L 644 LTFGDVVAV 2173 FABP7 645 LLYDAVHIV2899 GRIK3 646 ILSPTVVSI 3832 KIF11 647 SLGLFLAQV 51435 SCARA3 648LLWGNAIFL 547 KIF1A 649 ALAFKLDEV 201780 SLC10A4 650 AIMGFIGFFV 23480SEC61G 651 ILQDRLNQV 990 CDC6 652 TLWYRAPEV 1019, 1021 CDK4, CDK6 653TLISRLPAV 1104 RCC1 654 KILEDVVGV 22974 TPX2 655 ALMDKEGLTAL 26115 TANC2656 KLLEYIEEI 3161 HMMR 657 SLAERLFFQV 339983 NAT8L 658 LLQDRLVSV 57664PLEKHA4 659 ILFPDIIARA 64110 MAGEF1 660 AILDTLYEV 84725 PLEKHA8 661SLIDADPYL 890 CCNA2 662 KIQEILTQV 10643 IGF2BP3 663 KIQEMQHFL 4321 MMP12

The present invention furthermore generally relates to the peptidesaccording to the present invention for use in the treatment ofproliferative diseases, such as, for example non-small cell lung cancer,small cell lung cancer, kidney cancer, brain cancer, colon or rectumcancer, stomach cancer, liver cancer, pancreatic cancer, prostatecancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma,esophageal cancer, urinary bladder cancer, uterine cancer, gallbladdercancer, bile duct cancer.

Of particular interest and thus preferred is the peptide SEQ ID NO. 466(VLIANLEKL) and its uses in the immunotherapy of ovarian cancer,non-small cell lung cancer, small cell lung cancer, kidney cancer, braincancer, colon or rectum cancer, stomach cancer, liver cancer, pancreaticcancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma,melanoma, esophageal cancer, urinary bladder cancer, uterine cancer,gallbladder cancer, bile duct cancer, and preferably ovarian cancer.

Particularly preferred are the peptide—alone or in combination—accordingto the present invention selected from the group consisting of SEQ IDNO: 1, 11, 427, 408, 198, 512, 519, and 587 and their uses in theimmunotherapy of ovarian cancer, non-small cell lung cancer, small celllung cancer, kidney cancer, brain cancer, colon or rectum cancer,stomach cancer, liver cancer, pancreatic cancer, prostate cancer,leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophagealcancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bileduct cancer, and preferably ovarian cancer.

Particularly preferred are the peptide—alone or in combination—accordingto the present invention selected from the group consisting of SEQ IDNO: 3, 4, 5, 6, 8, 10, 12, 14, 15, 18, 20, 25, 29, 32, 37, 38, 39, 41,44, 45, 52, 53, 54, 57, 64, 69, 72, 73, 77, 78, 83, 89, 90, 91, 93, 94,96, 99, 100, 102, 104, 106, 107, 109, 113, 114, 117, 120, 123, 124, 136,137, 138, 139, 141, 143, 148, 150, 151, 157, 158, 160, 163, 165, 166,170, 171, 173, 175, 179, 180, 184, 185, 187, 189, 191, 192, 193, 194,195, 196, 200, 202, 204, 206, 209, 211, 215, 216, 217, 218, 219, 221,224, 225, 226, 230, 231, 232, 233, 234, 235, 238, 239, 243, 244, 245,247, 248, 250, 253, 258, 266, 267, 269, 301, 306, 347, 348, 350, 365,367, 369, 378, 380, 426, 430, 432, 433, 438, 441, 442, 444, 449, 451,455, 460, 461, 462, 463, 465, 467, 468, 470, 471, 478, 479, 481, 482,484, 485, 489, 491, 494, 498, 505, 509, 511, 514, 515, 516, 518, 522,532, 542, 547, 548, 552, 560, 578, and 620 and their uses in theimmunotherapy of ovarian cancer, non-small cell lung cancer, small celllung cancer, kidney cancer, brain cancer, colon or rectum cancer,stomach cancer, liver cancer, pancreatic cancer, prostate cancer,leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophagealcancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bileduct cancer, and preferably ovarian cancer.

Particularly preferred are the peptides—alone or incombination—according to the present invention selected from the groupconsisting of SEQ ID NO: 1 to SEQ ID NO: 640. More preferred are thepeptides—alone or in combination—selected from the group consisting ofSEQ ID NO: 1 to SEQ ID NO: 259 (see Table 1), and their uses in theimmunotherapy of ovarian cancer, non-small cell lung cancer, small celllung cancer, kidney cancer, brain cancer, colon or rectum cancer,stomach cancer, liver cancer, pancreatic cancer, prostate cancer,leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophagealcancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bileduct cancer, and preferably ovarian cancer.

As shown in the following Table 4A and B, many of the peptides accordingto the present invention are also found on other tumor types and can,thus, also be used in the immunotherapy of other indications. Also referto FIGS. 1A-1AE and Example 1.

TABLE 4A Peptides according to the present invention and their specific uses in otherproliferative diseases, especially in other cancerous diseases. The table shows forselected peptides on which additional tumor types they were found and either over-presented on more than 5% of the measured tumor samples, or presented on more than5% of the measured tumor samples with a ratio of geometric means tumor vs normaltissues being larger than 3. Over-presentation is defined as higher presentation on thetumor sample as compared to the normal sample with highest presentation. Normaltissues against which over-presentation was tested were: adipose tissue, adrenal gland,artery, bone marrow, brain, central nerve, colon, duodenum, esophagus, gallbladder,heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas,peripheral nerve, peritoneum, pituitary, pleura, rectum, salivary gland, skeletal muscle,skin, small intestine, spleen, stomach, thymus, thyroid gland, trachea, ureter, urinarybladder, vein. J = phospho-serine SEQ ID No SequenceOther relevant organs/cancerous diseases    1 SLMEPPAVLLLNSCLC, SCLC, Esophageal Cancer   2 SLLEADPFL Esophageal Cancer   6VLVSDGVHSV SCLC, Brain Cancer, BrCa, MCC, Esophageal Cancer   7SLVGLLLYL RCC, PC, BrCa   9 GAAKDLPGVRCC, GC, HCC, Urinary bladder Cancer  10 FLATFPLAAVUrinary bladder Cancer  11 KIFEMLEGV NSCLC  14 AAYGGLNEKSFVHCC, Urinary bladder Cancer  17 GLLPGDRLVSV NSCLC, SCLC, BrCa  19FMVDNEAIYDI SCLC, CRC, HCC, Leukemia, Melanoma, EsophagealCancer, Urinary bladder Cancer  20 RMIEYFIDV SCLC, HCC, MCC  22IMEENPGIFAV CRC, Leukemia, Melanoma  24 SLSDGLEEVCRC, PC, Urinary bladder Cancer  26 ALLELAEELLeukemia, Esophageal Cancer  27 ILADIVISANSCLC, SCLC, PC, BrCa, Esophageal Cancer  28 QLLDETSAITLSCLC, HCC, Leukemia, Urinary bladder Cancer  31 YLAPELFVNVSCLC, GC, Leukemia, Melanoma  32 KLDDLTQDLTV HCC,  33 VLLSLLEKV Leukemia 34 ILVEADSLWVV SCLC, PrC, Leukemia, Melanoma  36 YVLEDLEVTVSCLC, HCC, Leukemia  38 FLLEDDIHVS SCLC, Leukemia, Melanoma  45SLWQDIPDV NSCLC, SCLC  47 ILLSVPLLVVSCLC, Leukemia, Gallbladder Cancer, Bile Duct Cancer  48 ALAELYEDEVSCLC, Brain Cancer, HCC, Leukemia, Melanoma, Uterine Cancer  49YLPAVFEEV Leukemia  51 LLPDLEFYVSCLC, PrC, Gallbladder Cancer, Bile Duct Cancer  54 SLLEQGKEPWMVSCLC, HCC, Gallbladder Cancer, Bile Duct Cancer  55 SLLDLETLSL SCLC  56KLYEGIPVLL BrCa  57 TLAELQPPVQL NSCLC, SCLC, HCC, Leukemia, Melanoma,Esophageal Cancer  58 FLDTLKDLINSCLC, SCLC, GC, CRC, HCC, Leukemia, Melanoma,Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer  59 IMEDIILTLSCLC, Leukemia, BrCa  60 SLTIDGIYYV SCLC, Prostate, Leukemia  61FLQGYQLHL NSCLC, SCLC, BrCa, Melanoma, Esophageal Cancer  62VLLDVSAGQLLM NSCLC, Melanoma  63 YLLPSGGSVTLHCC, Melanoma, Esophageal Cancer  64 YAAPGGLIGVHCC, PC, Melanoma, Esophageal Cancer, GallbladderCancer, Bile Duct Cancer  65 LKVNQGLESLNSCLC, SCLC, PC, Leukemia, BrCa, Esophageal Cancer  66 FLDENIGGVAVSCLC, HCC  68 SLMELPRGLFL Brain Cancer  69 FQLDPSSGVLVTVEsophageal Cancer  72 SLLELDGINL NSCLC, SCLC, Prostate  74 ALLDPEVLSIFVNSCLC, Leukemia, Melanoma  75 GLLEVMVNL SCLC  76 ILIDSIYKVSCLC, CRC, BrCa  77 ILVEADGAWVV Melanoma, Esophageal Cancer  79SLFIGEKAVLL NSCLC, SCLC, CRC, Leukemia, Esophageal Cancer,Urinary bladder Cancer  80 FLYDNLVESL Leukemia  82 FLSSVTYNL SCLC,  84VTFGEKLLGV NSCLC, CRC, PC, PrC, Gallbladder Cancer, Bile Duct Cancer  85KMSELRVTL SCLC, Esophageal Cancer  86 NLIGKIENV Colon, Rectum  87ALPEAPAPLLPHIT HCC PC Urinary bladder Cancer, Gallbladder Cancer,Bile Duct Cancer  88 FLLVGDLMAV SCLC  91 IMQDFPAEIFL SCLC  92YLIPFTGIVGL SCLC, HCC, Leukemia, Melanoma  93 LLQAIKLYL BrCa  94YLIDIKTIAI HCC  95 SVIPQIQKV PC, Esophageal Cancer  97 SLINGSFLVNSCLC, RCC, CRC, HCC, PC, Melanoma, Esophageal Cancer  98 LIIDQADIYLNSCLC, SCLC, RCC, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer 101ILVGGGALATV Melanoma, Urinary bladder Cancer 103 TLAEEVVALSCLC, BrCa, Esophageal Cancer 104 STMEQNFLL NSCLC, 105 LLLEHSFEINSCLC, Melanoma 106 LLYDAVHIVSV Brain Cancer 107 FLQPVDDTQHLMelanoma, Esophageal Cancer 108 ALFPGVALLLA SCLC, HCC, Endometrium 110FLSQVDFEL BrCa 117 ILPDGEDFLAV SCLC 118 KLIDNNINV Brain Cancer 119FLYIGDIVSL Leukemia 121 GVVDPRAISVL Esophageal Cancer 123 NLWDLTDASVVSCLC, Prostate 125 VQIHQVAQV NSCLC, SCLC, HCC, PC, Esophageal Cancer,Gallbladder Cancer, Bile Duct Cancer 126 VLAYFLPEANSCLC, SCLC, CRC, PC, Leukemia, Esophageal Cancer, Uterine Cancer 127KIGDEPPKV NSCLC, SCLC, Brain Cancer, PC, Esophageal Cancer,Uterine Cancer 128 YLFDDPLSAV Leukemia, Esophageal Cancer 129GLLDGGVDILL HCC, Leukemia, Esophageal Cancer, Uterine Cancer 130FLWNGEDSALL PC 131 FVPPVTVFPSL BrCa 132 LLVEQPPLAGV Leukemia 134YLQELIFSV Endometrium 135 ALSEVDFQL SCLC, Brain Cancer 137 TLVLTLPTV PC139 SVMEVNSGIYRV HCC, MCC 141 YLDFSNNRL SCLC, BrCa 142 FLFATPVFI SCLC143 LLLDITPEI NSCLC, Brain Cancer, HCC, PC, BrCa, Melanoma,Esophageal Cancer 144 YIMEPSIFNTLHCC, Leukemia, Melanoma, Urinary bladder Cancer 145 FLATSGTLAGI Prostate146 SLATAGDGLIEL Urinary bladder, Endometrium 148 ALNPEIVSVEsophageal Cancer, Urinary bladder Cancer 149 NLLELFVQLSCLC, Leukemia, BrCa, Urinary bladder Cancer, Uterine Cancer 150RLWEEGEELEL NSCLC, Melanoma, Esophageal Cancer 151 KILQQLVTL Endometrium152 ILFEDIFDV SCLC, Endometrium 153 FLIANVLYLSCLC, Urinary bladder Cancer, Uterine Cancer 154 ALDDGTPAL HCC 155RVANLHFPSV Melanoma, Esophageal Cancer 157 SLNDEVPEVNSCLC, Brain Cancer, HCC, Esophageal Cancer, Uterine Cancer 159GLVGNPLPSV HCC, Leukemia 161 ALLEGVNTV NSCLC, Leukemia 163 ALDEMGDLLQLHCC 166 YLNHLEPPV SCLC, HCC, Leukemia, Esophageal Cancer 167 KVLEVTEEFGVNSCLC, HCC, Melanoma 169 NLPEYLPFV SCLC, BrCa, Urinary bladder Cancer170 RLQETLSAA HCC, Esophageal Cancer 171 LLLPLQILL SCLC 174 ALAQYLITABrain Cancer, HCC, PrC, Esophageal Cancer, Urinary bladder Cancer 176YLMEGSYNKVFL NSCLC, SCLC, CRC, HCC, Melanoma 177 YLLPEEYTSTLMelanoma, Esophageal Cancer 178 ALTEIAFVV CRC, HCC, PrC 179 KVLNELYTVNSCLC 183 FGLDLVTEL NSCLC, SCLC, RCC, GC, PC, Leukemia, BrCa, Melanoma184 YLMDINGKMWL NSCLC, SCLC, Melanoma 186 TLFFQQNAL Prostate, 188GLFPVTPEAV Colon, Rectum, HCC 190 FLSSLTETI Urinary bladder Cancer 195GLFADLLPRL NSCLC 197 ALGPEGGRV HCC 198 KTINKVPTV NSCLC, HCC 199ALQDVPLSSV Melanoma 200 LLFGSVQEVSCLC, PC, PrC, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer201 RLVDYLEGI NSCLC, HCC, Esophageal Cancer 204 KIAENVEEVNSCLC, HCC, PC, Leukemia, BrCa, Esophageal Cancer 205 SLYPGTETMGLSCLC, Gallbladder, Bile duct 207 GLTSTNAEVHCC, PrC, Esophageal Cancer, Uterine Cancer 208 KISPVTFSV HCC 209KLIESKHEV Brain Cancer, HCC 210 LLLNAVLTV Urinary bladder Cancer 212ALWDQDNLSV HCC, PrC, BrCa, Urinary bladder Cancer 213 VTAAYMDTVSLNSCLC, SCLC, HCC, Melanoma, Esophageal Cancer,Gallbladder Cancer, Bile Duct Cancer 214 FLLDLDPLLLSCLC, HCC, Leukemia, Uterine Cancer 216 NLWEDPYYLSCLC, PrC, BrCa, Urinary bladder Cancer 217 ALIHPVSTVNSCLC, RCC, HCC, Melanoma, Esophageal Cancer 218 SALEELVNV RCC 222NLIENVQRL NSCLC, RCC, CRC, HCC, Melanoma, EsophagealCancer, Urinary bladder Cancer 223 ALLENIALYLEsophageal Cancer, Urinary bladder Cancer 226 MLYVVPIYL BrCa 228AMQEYIAVV NSCLC, SCLC, Uterine Cancer, Gallbladder Cancer,Bile Duct Cancer 229 RLPGPLGTV HCC, Esophageal Cancer, Endometrium 230ILVDWLVEV Melanoma, Endometrium 233 VLSETLYEL SCLC, Endometrium 234ALMEDTGRQML NSCLC, SCLC, HCC, Esophageal Cancer 235 YLNDLHEVLLEsophageal Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer237 ALLEASGTLLL SCLC, HCC, PrC, Leukemia, Uterine Cancer,Gallbladder Cancer, Bile Duct Cancer 240 ILLEQAFYL SCLC 241 SLVEVNPAYSVProstate, Gallbladder, Bile duct 242 AIAYILQGVSCLC, Leukemia, BrCa, Esophageal Cancer, Urinary bladder Cancer 243LLLNELPSV Colon, Rectum, Esophageal Cancer 247 VLLPNDLLEKV Brain Cancer248 FLFPNQYVDV NSCLC, SCLC, HCC, Leukemia, Melanoma 249 LLDGFLVNV SCLC251 ALYTGFSILV SCLC, Leukemia, Melanoma 252 LLIGTDVSLPrC, Leukemia, Esophageal Cancer, Urinary bladder Cancer 253 GLDAATATVProstate, Leukemia 255 VLASYNLTV BrCa 256 FLPPEHTIVYISCLC, HCC, Leukemia, Melanoma 257 SIFSAFLSVStomach, Urinary bladder Cancer 258 ELAERVPAI Esophageal Cancer 262LLWGDLIWL Leukemia 263 LLVSNLDFGV NSCLC, SCLC, RCC, Leukemia 264SLQEQLHSV NSCLC, SCLC, PrC, BrCa, Melanoma, Esophageal Cancer 266KITDTLIHL BrCa 267 ALQDFLLSV HCC, Esophageal Cancer, Endometrium 268IAGPGLPDL NSCLC, RCC, BrCa 269 RVLEVGALQAV HCC 270 LLLDEEGTFSL Leukemia271 LVYPLELYPA RCC, HCC, Leukemia, BrCa, Esophageal Cancer,Urinary bladder Cancer 272 ALGNTVPAV PC, Leukemia, Endometrium 273NLFQSVREV HCC, BrCa 275 YLVYILNELRCC, GC, HCC, PC, Leukemia, Esophageal Cancer 276 ALFTFSPLTV Leukemia277 LLPPLESLATV SCLC, Leukemia, Melanoma 279 ALWGGTQPLLSCLC, Brain Cancer, Esophageal Cancer 280 VLPDPEVLEAV Prostate, Leukemia282 LLADVVPTT Leukemia, Melanoma 283 ALYIGDGYVIHLASCLC, BrCa, MCC, Melanoma 284 ILLSQTTGV Prostate, Leukemia 285 QLLHVGVTVNSCLC, RCC, CRC, Leukemia, Esophageal Cancer 286 YLFPGIPEL SCLC, HCC 287FLNEFFLNV NSCLC, Leukemia, Melanoma, Esophageal Cancer 288 NLINEINGVSCLC, PrC, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer 289VLLEIEDLQV Leukemia, BrCa 290 GLLDLNNAILQL HCC 291 GLDSNLKYILVPC, Melanoma 292 LLWEAGSEA Brain Cancer, PC 294 ILDPFQYQLHCC, Esophageal Cancer 296 FMEGAIIYV SCLC, Leukemia 298 VMITKLVEVUrinary bladder Cancer 299 YLLETSGNL Leukemia, Urinary bladder Cancer300 ALLGQTFSL SCLC, Brain Cancer, CRC 301 FLVEDLVDSL SCLC, HCC, Leukemia303 AILPQLFMV NSCLC, RCC, CRC, BrCa, Esophageal Cancer,Urinary bladder Cancer 306 ALVNVQIPL HCC, Esophageal Cancer 308SQYSGQLHEV Leukemia, Gallbladder, Bile duct 309 GLFDGVPTTAHCC, Leukemia, BrCa, Melanoma 310 FLVDTPLARA Urinary bladder Cancer 311RLYTGMHTV RCC, CRC, PC, Esophageal Cancer, Urinary bladder Cancer 312IISDLTIAL SCLC, PC 313 VLFDDELLMVNSCLC, RCC, Brain Cancer, HCC, Esophageal Cancer 314 ALIAEGIALVSCLC, Melanoma 315 YLQDVVEQA SCLC, Endometrium 316 ILLERLWYV Melanoma317 SLAALVVHV Esophageal Cancer, Urinary bladder Cancer 318 GLINTGVLSVColon, Rectum 319 SLEPQIQPV NSCLC, CRC, Leukemia, Esophageal Cancer 320KMFEFVEPLL Colon, Rectum 321 GLFEDVTQPGILL Leukemia, Melanoma 322TLMTSLPAL SCLC, 323 IQIGEETVITV NSCLC, SCLC, PrC, Leukemia, Melanoma,Esophageal Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer324 FLYDEIEAEV Leukemia 325 FIMPATVADATAV Leukemia 327 GLAPFTEGISFV HCC328 ALNDQVFEI SCLC, Brain Cancer, HCC, Esophageal Cancer, Uterine Cancer329 FLVTLNNVEV Melanoma 330 QLALKVEGV Esophageal Cancer 331 KVDTVWVNVSCLC, Leukemia, BrCa, Melanoma, Urinary bladder Cancer 332 YLISELEAABrain Cancer, HCC, PC, PrC, Esophageal Cancer, Uterine Cancer 333FLPDANSSV NSCLC, Brain Cancer, PrC, Leukemia, BrCa,Esophageal Cancer, Urinary bladder Cancer 334 TLTKVLVALUrinary bladder Cancer 335 YSLSSVVTVNSCLC, GC, PC, BrCa, Gallbladder Cancer, Bile Duct Cancer 336 ILLTAIVQVBrCa, Esophageal Cancer 338 SVLEDPVHAV NSCLC, SCLC, HCC, Melanoma 339GLWEIENNPTVKA HCC, Melanoma, Endometrium 340 ALLSMTFPLBrain Cancer, HCC, BrCa 341 SQIALNEKLVNL SCLC, HCC 342 HIYDKVMTVColon, Rectum 343 SLLEVNEESTV NSCLC, Leukemia, Melanoma 344 YLQDQHLLLTVSCLC, Melanoma 345 VIWKALIHL SCLC 346 LLDSKVPSVSCLC, HCC, PC, Esophageal Cancer, Urinary bladderCancer, Gallbladder Cancer, Bile Duct Cancer 347 SLFKHDPAAWEANSCLC, HCC, Esophageal Cancer, Urinary bladder Cancer 348 ILLDVKTRLNSCLC, CRC, Esophageal Cancer, Urinary bladder Cancer 349 SLTEYLQNVColon, Rectum, HCC 351 SLIPNLRNV PC 354 LILEGVDTV Esophageal Cancer 355SIQQSIERLLV NSCLC, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer 356KLLGKLPEL NSCLC, CRC, Esophageal Cancer 357 SMHDLVLQVBrain Cancer, PC, Endometrium 358 ALDEYTSELBrain Cancer, PC, Leukemia, BrCa, Uterine Cancer 359 YLLPESVDLNSCLC, CRC, HCC, Esophageal Cancer 360 ALDJGASLLHLRCC, HCC, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer 361ALYELEGTTV Esophageal Cancer 362 TLYGLSVLL BrCa 363 KVLDVSDLESVUrinary bladder, Endometrium 364 LLQNEQFEL RCC 365 YVIDQGETDVYVLeukemia, Melanoma 366 RLLDMGETDLML SCLC, Leukemia, Melanoma 367SLQNHNHQL HCC, Urinary bladder Cancer 369 GLFPEHLIDV HCC 370 SLLQDLVSVHCC 371 FLQAHLHTA BrCa 372 TMLLNIPLV SCLC, HCC, PC, PrC, BrCa 373SLLEDKGLAEV NSCLC, SCLC, Leukemia, BrCa, MCC, Melanoma 374 FLLQQHLISALeukemia 375 SLTETIEGV BrCa, Esophageal Cancer 376 AMFESSQNVLLColon, Rectum 378 ALGYFVPYV HCC 379 IMEGTLTRV Leukemia 381 FIDEAYVEVLeukemia 382 ALQNYIKEA Esophageal Cancer 383 ALLELENSVTL HCC 384ILFANPNIFV CRC, Leukemia, Melanoma 385 SLLEQGLVEANSCLC, SCLC, Brain Cancer, HCC, EsophagealCancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer 386ILFRYPLTI Urinary bladder Cancer 387 ALFQATAEV HCC, Esophageal Cancer388 SLTIDGIRYV SCLC, Melanoma 389 LLADVTHLL Brain Cancer, Endometrium390 ALFMKQIYL Urinary bladder Cancer 391 YVYPQRLNFV Leukemia, Melanoma393 GLLDTQTSQVLTA HCC, BrCa, Esophageal Cancer, Urinary bladder Cancer394 LLAVIGGLVYL NSCLC, SCLC, RCC, HCC, PrC, Leukemia, Melanoma,Urinary bladder Cancer 395 ALALGGIAVVNSCLC, CRC, HCC, PrC, Leukemia, BrCa, Melanoma,Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer 396 ALLPDLPALHCC, BrCa 397 YLFGERLLEC Colon, Rectum, Leukemia 398 KLLEEDGTIITLColon, Rectum, PC 399 YLFEPLYHV SCLC 400 SLLTEQDLWTV Leukemia 401ILLDDTGLAYI SCLC, HCC, Leukemia, BrCa, Melanoma 403 KLYDRILRV NSCLC, RCC404 AIDIJGRDPAV SCLC, Leukemia 405 ALYDVFLEV PC, Esophageal Cancer 406SVQGEDLYLV HCC, Endometrium 407 YLMDLINFL PC, Prostate 408 VLDDSIYLVLeukemia 409 LLDAMNYHL HCC, Leukemia 410 VLSDVIPJISCLC, RCC, Brain Cancer, GC, HCC, PC, PrC,Leukemia, Melanoma, Esophageal Cancer 411 LLAHLSPEL HCC 412 YLDDLNEGVYILeukemia, Melanoma 415 LLDKVYSSV NSCLC, HCC, Leukemia, Esophageal Cancer418 ALAELENIEV SCLC, MCC 419 GQYEGKVSSV HCC 420 FMYDTPQEVSCLC, HCC, BrCa 421 RLPETLPSL NSCLC, SCLC, GC, CRC, PC 422 FLPKLLLLABrCa 423 GLDGPPPTV HCC, PC, BrCa, Urinary bladder Cancer, UterineCancer, Gallbladder Cancer, Bile Duct Cancer 424 TLLDALYEIRCC, Esophageal Cancer, Endometrium 425 FLYEKSSQVBrain Cancer, Endometrium 426 RLADKSVLV Colon, Rectum 427 ALLPLSPYLNSCLC, SCLC, HCC, PC, BrCa, Uterine Cancer 428 KLGHTDILVGVNSCLC, SCLC, CRC, HCC, Leukemia 429 GLVNDLARV NSCLC, HCC 430 HLYSSIEHLTTNSCLC, CRC, HCC, MCC, Esophageal Cancer 431 SLVNVVPKLNSCLC, SCLC, RCC, Brain Cancer, Melanoma, Esophageal Cancer 432TLIEESAKV Prostate 433 AMLNEPWAV SCLC 434 KVSNSGITRV NSCLC 435 WLMPVIPALSCLC 437 SMAPGLVIQAV SCLC, Prostate 439 YLLQEIYGI SCLC, BrCa 440ALADGVTMQV Gallbladder, Bile duct 441 ALLENPKMELNSCLC, SCLC, CRC, HCC, MCC, Esophageal Cancer 443 GLWEIENNPTVNSCLC, SCLC, HCC, PC, PrC, Melanoma 444 GLLRDEALAEVNSCLC, SCLC, CRC, Melanoma, Esophageal Cancer 446 QLIPALAKVNSCLC, SCLC, PrC, BrCa, MCC, Uterine Cancer 447 QLVPALAKVNSCLC, SCLC, HCC, PrC, Esophageal Cancer, Urinary bladder Cancer 448NLLETKLQL Colon, Rectum, Leukemia 449 KLAEGLDIQL SCLC, Colon, Rectum 450FMIDASVHPTL NSCLC, SCLC, RCC, Brain Cancer, CRC, HCC,Leukemia, Melanoma, Esophageal Cancer 451 LLLLDTVTMQV SCLC, HCC 452ILLEHGADPNL HCC, Leukemia, Melanoma 454 KLPPPPPQA NSCLC, SCLC 455SLLKEPQKVQL RCC 456 LLIGHLERV NSCLC, Brain Cancer, CRC, 457 SLLPGNLVEKVNSCLC, HCC, Leukemia, Melanoma 458 SLIDKLYNI NSCLC, Colon, Rectum, 459ALITEVVRL NSCLC, CRC, PC, Leukemia, BrCa, Esophageal Cancer 461VMFRTPLASV SCLC, Melanoma, Esophageal Cancer 463 SLVESHLSDQLTLNSCLC, SCLC, HCC, Melanoma 464 ALNDCIYSV Brain Cancer, HCC, PC 465QLCDLNAEL HCC, Esophageal Cancer 466 VLIANLEKL BrCa, Esophageal Cancer468 YLRSVGDGETV Leukemia, Melanoma 469 YLASDEITTV SCLC, 472 KLLEVSDDPQVHCC, MCC, Melanoma, Esophageal Cancer 473 AMATESILHFASCLC, Brain Cancer, CRC, HCC, MCC, Gallbladder Cancer, Bile Duct Cancer474 YLDPALELGPRNV NSCLC, SCLC, Brain Cancer, HCC, MCC, Melanoma 475LLLNEEALAQI SCLC, Leukemia 476 ALMERTGYSMV HCC 477 ALLPASGQIALNSCLC, HCC, Esophageal Cancer, Urinary bladder Cancer 478 YLLHEKLNLColon, Rectum, 479 SLFGNSGILENVNSCLC, SCLC, HCC, MCC, Urinary bladder Cancer 480 ALLEDSCHYLNSCLC, CRC, HCC, Leukemia, Esophageal Cancer 481 GLIEDYEALL SCLC 483ALTDIVSQV Urinary bladder Cancer 484 SLIEKVTQL HCC 485 NVPDSFNEV Stomach486 AVMESIQGV NSCLC, HCC, PrC, Leukemia, Esophageal Cancer,Urinary bladder Cancer, Uterine Cancer 487 LLINSVFHV Melanoma 488FLAEDPKVTL Leukemia 489 KMWEELPEVV NSCLC, HCC, Leukemia 490 FLLQHVQELLeukemia 491 GLNDRSDAV Esophageal Cancer, Endometrium 492 SLFDGFADGLGVNSCLC, SCLC, Brain Cancer, HCC, PrC, Esophageal Cancer 493 GLLGEKTQDLIGVNSCLC, SCLC 494 ALQPEPIKV Urinary bladder, Gallbladder, Bile duct 495FIFSEKPVFV Urinary bladder Cancer 496 FLVEKQPPQV Leukemia, Melanoma 497GLLEKLTAI NSCLC, RCC, Esophageal Cancer, Uterine Cancer 498 KLWTGGLDNTVHCC, Esophageal Cancer 499 KIFDIDEAEEGV PC, Melanoma, Esophageal Cancer500 SLMEDQVLQL SCLC, Colon, Rectum 501 LLDPNVKSIFVNSCLC, SCLC, Brain Cancer, HCC, PrC, MCC,Melanoma, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer 502RLLAQVPGL RCC, Urinary bladder Cancer 503 SLNHFTHSV NSCLC, Leukemia 504GLSDGNPSL Leukemia, BrCa 505 SLAPGDVVRQV Esophageal Cancer 506 KLLGKVETANSCLC, Brain Cancer, Leukemia, Esophageal Cancer 507 KLIDDQDISISLLeukemia 508 ILAQEQLVVGV Leukemia, Esophageal Cancer 510 KLYSVVSQLColon, Rectum, Leukemia 513 SLWPSPEQL HCC, Esophageal Cancer 514ILVDWLVQV NSCLC, SCLC, RCC, Brain Cancer, GC, CRC, HCC,Melanoma, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer 517LLMPIPEGLTL NSCLC, SCLC, HCC, Melanoma 518 KLNAEVACVCRC, PrC, Esophageal Cancer 520 LAVHPSGVAL Leukemia 521 MLLTKLPTINSCLC, SCLC, CRC, HCC, BrCa, Melanoma, Urinary bladder Cancer 522TLWYRSPEV SCLC 523 YQIPRTFTL SCLC, Brain Cancer, HCC, Leukemia, Melanoma525 VLLEAGEGLVTI Melanoma 526 RLAEVGQYEQVNSCLC, HCC, MCC, Gallbladder Cancer, Bile Duct Cancer 527 FLLEPGNLEVUrinary bladder Cancer 528 SVAEGRALMSVBrain Cancer, CRC, HCC, Esophageal Cancer 529 LLADELITVProstate, Leukemia, Urinary bladder Cancer 530 VMYADIGGMDISCLC, Melanoma 531 YTLPIASSIRL SCLC, CRC, HCC 533 RMVAEIQNVLeukemia, Esophageal Cancer 535 KLIAQNLEL Colon, Rectum 536 YLVEGRFSVLeukemia 538 LLLAHIIAL NSCLC, Brain Cancer, HCC 539 ALFDAQAQVNSCLC, SCLC, Brain Cancer, HCC, PC, PrC, BrCa,Esophageal Cancer, Urinary bladder Cancer, UterineCancer, Gallbladder Cancer, Bile Duct Cancer 540 ALIPETTTLTVHCC, PC, Melanoma 541 SMLEPVPELNSCLC, SCLC, Brain Cancer, CRC, HCC, Esophageal Cancer 542 RVWDISTVSSVSCLC, Leukemia, Melanoma, Esophageal Cancer 543 GLLPTPITQQASLEsophageal Cancer 544 LLWDVPAPSL Leukemia, Melanoma 545 LLADLLHNVNSCLC, SCLC, Colon, Rectum 546 VMIAGKVAVV Colon, Rectum, HCC 549AMLENASDIKL Melanoma 550 FLYDEIEAEVNL Leukemia, Melanoma 551 KLYESLLPFASCLC, HCC, PrC, Melanoma 552 GLLDLPFRVGVSCLC, Brain Cancer, Leukemia, Melanoma 554 LLMPSSEDLLLNSCLC, SCLC, CRC, HCC, PrC, BrCa, EsophagealCancer, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer 555YVLEGLKSV SCLC, Melanoma 556 FLTDLEDLTL SCLC, Leukemia 557 KLYDDMIRLColon, Rectum, 558 GLLENIPRVNSCLC, SCLC, RCC, Brain Cancer, HCC, Leukemia,Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer 559 VTVPPGPSLLeukemia 560 ALWDIETGQQTTT SCLC, HCC, Melanoma, Esophageal Cancer 561YLQLTQSEL SCLC, Leukemia, Esophageal Cancer, GallbladderCancer, Bile Duct Cancer 563 WLLPYNGVTV SCLC, Melanoma 564 TVTNAVVTVRCC, GC, HCC, Melanoma 565 ALQETPTSVSCLC, Melanoma, Esophageal Cancer, Uterine Cancer 566 VIADGGIQNVLeukemia, Melanoma, Endometrium 567 SLLPLDDIVRV Leukemia 568 TLYDIAHTPGVNSCLC, SCLC, CRC, Melanoma, Esophageal Cancer 571 LLLTTIPQIProstate, Leukemia 572 ALADLIEKELSV Leukemia 573 ILVANAIVGVNSCLC, HCC, Leukemia, Melanoma 574 YLLQEPPRTV SCLC 575 YLISQVEGHQVCRC, HCC, MCC, Melanoma, Esophageal Cancer 576 ILLNNSGQIKLNSCLC, CRC, HCC, Leukemia, BrCa, Melanoma, Esophageal Cancer 577VMFEDGVLMRL Colon, Rectum, Leukemia 578 FLDPGGPMMKLNSCLC, CRC, MCC, Melanoma 579 NLMEMVAQL NSCLC, CRC, HCC, Leukemia 580LLMENAERV CRC, Leukemia, BrCa, Melanoma 581 RLWNETVELSCLC, Colon, Rectum 583 ILANDGVLLAA HCC, Esophageal Cancer 584ALAEVAAMENV Melanoma 585 ALWDLAADKQTL Urinary bladder Cancer 586KLKPGDLVGV Brain Cancer, HCC 587 VMNDRLYAI Leukemia 588 SLLPLSHLVMelanoma, Esophageal Cancer 589 KLYPQLPAEINSCLC, SCLC, Brain Cancer, HCC, Leukemia, MCC,Melanoma, Esophageal Cancer 590 SLIEKLWQT SCLC, Brain Cancer 591SMAELDIKL Leukemia, Esophageal Cancer, Endometrium 592 RLLJAAENFLSCLC, Brain Cancer, BrCa, Esophageal Cancer 593 GLPRFGIEMV Brain Cancer594 IMLKGDNITL Esophageal Cancer 595 VLLSIYPRVNSCLC, SCLC, RCC, Leukemia, BrCa 596 ALLDQTKTLAESAL Leukemia, Melanoma597 KLLEGQVIQL NSCLC, SCLC, CRC, HCC, BrCa 599 YLLNDASLISVNSCLC, CRC, HCC, Melanoma, Uterine Cancer 600 ALAAPDIVPAL Leukemia 601SAFPFPVTV Stomach, Leukemia, Esophageal Cancer 602 YLLEQIKLIEVNSCLC, SCLC 603 FLIEPEHVNTV HCC, PC, Leukemia, Melanoma 604 SILDRDDIFVLeukemia 606 ALWETEVYI SCLC, Brain Cancer, HCC, PrC 607 RLYSGISGLELNSCLC 608 SLLSVSHAL RCC 609 ALWKQLLEL PC 610 LLAPTPYIIGVNSCLC, SCLC, RCC, Brain Cancer, CRC, HCC, PrC,Leukemia, BrCa, MCC, Melanoma, EsophagealCancer, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer 611YLLDDGTLVV HCC, Melanoma 613 RLLPPGAVVAV NSCLC, SCLC, HCC 614LLLPDQPPYHL Melanoma 616 VLIDEVESL NSCLC, SCLC, RCC, GC, BrCa, Melanoma,Esophageal Cancer, Urinary bladder Cancer 617 ALMYESEKVGVHCC, Gallbladder, Bile duct 618 VLFDSESIGIYV SCLC, Melanoma 619ALQDRVPLA Brain Cancer, CRC, Esophageal Cancer, Uterine Cancer 620KLLNKIYEA Brain Cancer 621 VLMDRLPSLL Melanoma 622 RLLGEEVVRVLQANSCLC, SCLC, CRC, Melanoma 624 FLQEEPGQLLLeukemia, Melanoma, Esophageal Cancer 625 VVLEGASLETV SCLC, Melanoma 626LLMATILHL SCLC, Melanoma, Urinary bladder Cancer, GallbladderCancer, Bile Duct Cancer 627 KLLETELLQEINSCLC, SCLC, CRC, HCC, MCC, Melanoma 628 KLWEFFQVDVSCLC, Brain Cancer, HCC 629 HLLNESPML SCLC, Esophageal Cancer 630LLSHVIVAL PC, Leukemia 631 FLDVFLPRVPC, Leukemia, Melanoma, Esophageal Cancer 632 YLIPDIDLKLNSCLC, SCLC, CRC, HCC, PC, Leukemia, Melanoma,Urinary bladder Cancer, Uterine Cancer 633 ALSRVSVNVMelanoma, Esophageal Cancer 634 VVAEFVPLI Brain Cancer, Leukemia 635SLDSTLHAV NSCLC, Brain Cancer, CRC, HCC, BrCa, Esophageal Cancer 637SIYGGFLLGV NSCLC, SCLC, HCC, PrC, BrCa, Uterine Cancer 638 KLIQESPTVSCLC, HCC, Prostate 639 SLFQNCFEL Leukemia 640 YLFSEALNAASCLC, GC, CRC, HCC, PrC, BrCa, MCC, EsophagealCancer, Urinary bladder Cancer, Uterine Cancer,Gallbladder Cancer, Bile Duct Cancer  NSCLC = non-small cell lungcancer, SCLC = small cell lung cancer, RCC = kidney cancer, CRC= colorectal cancer, GC = gastric cancer, HCC = liver cancer, PC= pancreatic cancer, PrC = prostate cancer, BrCa = breast cancer, MCC= Merkel cell carcinoma

TABLE 5BPeptides according to the present invention and their specific uses inother proliferative diseases, especially in other cancerous diseases(amendment of Table 4). The table shows, like Table 4A, for selectedpeptides on which additional tumor types they were found showingover-presentation (including specific presentation) on more than5% of the measured tumor samples, or presentation on more than 5%of the measured tumor samples with a ratio of geometric means tumorvs normal tissues being larger than 3. Over-presentation is defined ashigher presentation on the tumor sample as compared to the normalsample with highest presentation. Normal tissues against which over-presentation was tested were: adipose tissue, adrenal gland, artery,bone marrow, brain, central nerve, colon, duodenum, esophagus, eye,gallbladder, heart, kidney, liver, lung, lymph node, mononuclear whiteblood cells, pancreas, parathyroid gland, peripheral nerve,peritoneum, pituitary, pleura, rectum, salivary gland, skeletalmuscle, skin, small intestine, spleen, stomach, thyroid gland,trachea, ureter, urinary bladder, vein. SEQ ID NO. SequenceAdditional organs/cancerous diseases 1 SLMEPPAVLLLBRCA, Urinary Bladder Cancer, Uterine Cancer, AML, HNSCC 2 SLLEADPFLCLL, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer 3 SLASKLTTLUterine Cancer 5 HLTEVYPEL Urinary Bladder Cancer, Uterine Cancer 6VLVSDGVHSV Melanoma, Urinary Bladder Cancer, Uterine Cancer, HNSCC 7SLVGLLLYL Gallbladder Cancer and Bile Duct Cancer, AML 8 FTLGNVVGMYLMelanoma, Urinary Bladder Cancer, Uterine Cancer 9 GAAKDLPGVEsophageal Cancer 11 KIFEMLEGV Gallbladder Cancer and Bile Duct Cancer13 YLMDESLNL NSCLC, Brain Cancer, BRCA, Melanoma 14 AAYGGLNEKSFVCLL, Esophageal Cancer 15 VLLTFKIFL Uterine Cancer, NHL 16 VLFQGQASLMelanoma, Uterine Cancer, AML, NHL 18 YLVAKLVEVNSCLC, BRCA, Urinary Bladder Cancer, HNSCC 21 VLDELDMEL Melanoma 22IMEENPGIFAV CLL, Urinary Bladder Cancer, Gallbladder Cancerand Bile Duct Cancer 23 VLLDDIFAQL CLL, Uterine Cancer, AML 24 SLSDGLEEVNSCLC, BRCA, Melanoma, Uterine Cancer, HNSCC 26 ALLELAEELBRCA, Melanoma, Urinary Bladder Cancer, UterineCancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC 27ILADIVISA Melanoma, Uterine Cancer, Gallbladder Cancer andBile Duct Cancer 28 QLLDETSAITL CLL 29 KMLGIPISNILMVUrinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer 30LILDWVPYI Melanoma, Uterine Cancer, HNSCC 31 YLAPELFVNVBRCA, Uterine Cancer 32 KLDDLTQDLTVSCLC, Esophageal Cancer, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, HNSCC 33 VLLSLLEKVCLL, Melanoma 34 ILVEADSLWVV AML 36 YVLEDLEVTVNSCLC, CLL, BRCA, Melanoma, Urinary BladderCancer, Uterine Cancer, Gallbladder Cancer and BileDuct Cancer, NHL, HNSCC 38 FLLEDDIHVS CLL, Urinary Bladder Cancer, NHL40 TLLVKVFSV Melanoma 42 VLLQKIVSA Esophageal Cancer, AML 43 VLSSLEININHL 45 SLWQDIPDV BRCA, Urinary Bladder Cancer, HNSCC 47 ILLSVPLLVVCLL, Uterine Cancer 49 YLPAVFEEV CLL 51 LLPDLEFYVMelanoma, Urinary Bladder Cancer 54 SLLEQGKEPW NSCLC, CLL MV 57TLAELQPPVQL CLL, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 58 FLDTLKDLIUrinary Bladder Cancer, Uterine Cancer, AML, NHL 60 SLTIDGIYYVBRCA, Uterine Cancer 61 FLQGYQLHLUrinary Bladder Cancer, Uterine Cancer, GallbladderCancer and Bile Duct Cancer, NHL, HNSCC 63 YLLPSGGSVTLGallbladder Cancer and Bile Duct Cancer, HNSCC 64 YAAPGGLIGVNSCLC, SCLC, CLL, BRCA, Urinary Bladder Cancer,Uterine Cancer, AML, NHL, HNSCC 65 LKVNQGLESLMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML, NHL 66FLDENIGGVAV Melanoma, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC 67 TLLAEALVTVSCLC 69 FQLDPSSGVLV HNSCC TV 71 GILARIASV AML, NHL 72 SLLELDGINLBRCA, Uterine Cancer 73 NIFDLQIYV BRCA 75 GLLEVMVNLGallbladder Cancer and Bile Duct Cancer 76 ILIDSIYKV Uterine Cancer 77ILVEADGAWVV BRCA, Uterine Cancer, AML, NHL 78 SLFSSLEPQIQPVCLL, Melanoma, Urinary Bladder Cancer, AML, HNSCC 79 SLFIGEKAVLLCLL, BRCA, Melanoma, Gallbladder Cancer and BileDuct Cancer, AML, NHL, HNSCC 80 FLYDNLVESL CLL, NHL 81 FLFSQLQYLGallbladder Cancer and Bile Duct Cancer, AML 82 FLSSVTYNL Melanoma 83ILAPTVMMI Melanoma 84 VTFGEKLLGV Melanoma 88 FLLVGDLMAV Melanoma 91IMQDFPAEIFL CLL, BRCA, Melanoma, Gallbladder Cancer and BileDuct Cancer, AML, NHL, HNSCC 92 YLIPFTGIVGL CLL, AML, NHL, HNSCC 93LLQAIKLYL Urinary Bladder Cancer, Gallbladder Cancer and BileDuct Cancer 94 YLIDIKTIAI SCLC, Melanoma, Urinary Bladder Cancer 97SLINGSFLV CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer 98 LIIDQADIYLCLL, Urinary Bladder Cancer, Gallbladder Cancerand Bile Duct Cancer, AML, NHL 100 YLLSTNAQL Urinary Bladder Cancer 102YLFESEGLVL CLL, Melanoma 103 TLAEEVVAL Melanoma, HNSCC 104 STMEQNFLLSCLC, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC 105LLLEHSFEI Urinary Bladder Cancer, Gallbladder Cancer and BileDuct Cancer, NHL, HNSCC 107 FLQPVDDTQHLUterine Cancer, Gallbladder Cancer and Bile Duct Cancer 108 ALFPGVALLLAMelanoma 111 YVWGFYPAEV CLL, Uterine Cancer, NHL 117 ILPDGEDFLAVCLL, BRCA, Uterine Cancer, NHL 119 FLYIGDIVSL CLL, Melanoma 120ALLGIPLTLV Uterine Cancer 123 NLWDLTDASVVNSCLC, BRCA, Melanoma, Esophageal Cancer,Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC 124ALYETELADA CLL, Uterine Cancer, AML, NHL 126 VLAYFLPEACLL, BRCA, Urinary Bladder Cancer, GallbladderCancer and Bile Duct Cancer, AML, NHL, HNSCC 127 KIGDEPPKVBRCA, Melanoma, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, HNSCC 128 YLFDDPLSAVCLL, BRCA, Uterine Cancer, Gallbladder Cancer andBile Duct Cancer, AML, NHL, HNSCC 129 GLLDGGVDILL HNSCC 131 FVPPVTVFPSLUterine Cancer 132 LLVEQPPLAGV CLL, Melanoma 134 YLQELIFSV CLL, HNSCC137 TLVLTLPTV SCLC, CLL, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC 138 YQYPRAILSVNSCLC, AML 139 SVMEVNSGIYRVSCLC, CLL, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 140 YMDAPKAALMelanoma, AML 141 YLDFSNNRL CLL 144 YIMEPSIFNTL CLL, BRCA 146SLATAGDGLIEL BRCA 147 SLLEAVSFLGallbladder Cancer and Bile Duct Cancer, AML, HNSCC 148 ALNPEIVSVSCLC, CLL, Melanoma, NHL, HNSCC 150 RLWEEGEELELUterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC 151KILQQLVTL BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer 152ILFEDIFDV BRCA, Gallbladder Cancer and Bile Duct Cancer 153 FLIANVLYLHNSCC 154 ALDDGTPAL Uterine Cancer 155 RVANLHFPSV CLL, HNSCC 157SLNDEVPEV BRCA, Melanoma, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 159 GLVGNPLPSV BRCA160 FLFDEEIEQI BRCA 161 ALLEGVNTV AML 163 ALDEMGDLLQLBRCA, Gallbladder Cancer and Bile Duct Cancer, HNSCC 164 ALLPQPKNLTVMelanoma 166 YLNHLEPPV Brain Cancer, CLL, BRCA, AML, NHL 167 KVLEVTEEFGVBRCA, Urinary Bladder Cancer 170 RLQETLSAA Urinary Bladder Cancer, AML171 LLLPLQILL HNSCC 172 VLYSYTIITV SCLC, CLL, Uterine Cancer, NHL 173LLDSASAGLYL SCLC, Uterine Cancer, AML, NHL 174 ALAQYLITASCLC, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer 175YLFENISQL Esophageal Cancer, Urinary Bladder Cancer, HNSCC 176YLMEGSYNKVFL Urinary Bladder Cancer, Gallbladder Cancer and BileDuct Cancer 177 YLLPEEYTSTL NHL, HNSCC 178 ALTEIAFVVSCLC, CLL, BRCA, Melanoma, Uterine Cancer 179 KVLNELYTVCRC, BRCA, Melanoma, Uterine Cancer 180 FQIDPHSGLVTV SCLC 182 MLLEAPGIFLCLL 183 FGLDLVTEL CLL, Urinary Bladder Cancer, Uterine Cancer, AML,NHL, HNSCC 184 YLMDINGKMWLCLL, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL 185FLIDDKGYTL HNSCC 186 TLFFQQNAL PC, NHL, HNSCC 187 RQISIRGIVGVNSCLC, Urinary Bladder Cancer, Uterine Cancer, AML, HNSCC 188 GLFPVTPEAVUterine Cancer 190 FLSSLTETIBRCA, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer 191LLQEGQALEYV Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer 192KMLDGASFTL BRCA 193 QLLDADGFLNV SCLC, NHL 194 ALPLFVITV AML, HNSCC 195GLFADLLPRL PC, Uterine Cancer, AML, HNSCC 197 ALGPEGGRV Uterine Cancer198 KTINKVPTV SCLC, Brain Cancer, CRC, Urinary Bladder Cancer,Uterine Cancer, HNSCC 199 ALQDVPLSSV SCLC, Urinary Bladder Cancer 201RLVDYLEGI SCLC, Uterine Cancer, Gallbladder Cancer and BileDuct Cancer, AML 205 SLYPGTETMGL AML 206 VLQEGKLQKLANSCLC, SCLC, BRCA, Uterine Cancer, HNSCC QL 207 GLTSTNAEV AML 209KLIESKHEV Melanoma, Uterine Cancer 210 LLLNAVLTV SCLC, AML, NHL 211LLWPGAALL CLL, AML, NHL 214 FLLDLDPLLLBrain Cancer, CRC, CLL, Urinary Bladder Cancer 217 ALIHPVSTVBRCA, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer 218 SALEELVNV GC 224 TLIDAQWVLHNSCC 226 MLYVVPIYL SCLC, Melanoma, AML, NHL 227 ALMNTLLYLUterine Cancer, AML, HNSCC 228 AMQEYIAVV PC, Melanoma, HNSCC 229RLPGPLGTV BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer 230ILVDWLVEV Esophageal Cancer, Gallbladder Cancer and BileDuct Cancer, AML, NHL, HNSCC 233 VLSETLYEL BRCA, HNSCC 234 ALMEDTGRQMLBrain Cancer, Urinary Bladder Cancer, GallbladderCancer and Bile Duct Cancer, HNSCC 235 YLNDLHEVLLNSCLC, Urinary Bladder Cancer 236 GLLEAKVSLGallbladder Cancer and Bile Duct Cancer 237 ALLEASGTLLL BRCA, AML 238YLISFQTHI CLL 242 AIAYILQGVRCC, CRC, CLL, Melanoma, Uterine Cancer, AML, NHL, HNSCC 243 LLLNELPSVSCLC, BRCA, Melanoma, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC 244 SLFGGTEITIUterine Cancer 246 LLWEVVSQL BRCA 247 VLLPNDLLEKV Melanoma 248FLFPNQYVDV CLL, BRCA 249 LLDGFLVNV CLL, Melanoma, NHL 250 ALSEEGLLVYLBRCA, Melanoma 252 LLIGTDVSL CLL, NHL 256 FLPPEHTIVYICLL, Uterine Cancer 257 SIFSAFLSVMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML, NHL 258ELAERVPAI CLL, Urinary Bladder Cancer, Gallbladder Cancerand Bile Duct Cancer, AML, NHL, HNSCC 259 TLMRQLQQV Uterine Cancer 260TLLEGPDPAELLL AML 261 YVLEFLEEI RCC, CLL, BRCA 262 LLWGDLIWLCRC, PrC, CLL, Melanoma, AML 263 LLVSNLDFGVCRC, CLL, Urinary Bladder Cancer, AML, NHL 264 SLQEQLHSV Uterine Cancer266 KITDTLIHL Uterine Cancer 267 ALQDFLLSVNSCLC, SCLC, CRC, BRCA, Melanoma, UrinaryBladder Cancer, AML, NHL, HNSCC 268 IAGPGLPDL HCC, Uterine Cancer, NHL269 RVLEVGALQAV CLL 270 LLLDEEGTFSL CLL, BRCA, Melanoma, NHL 271LVYPLELYPA Gallbladder Cancer and Bile Duct Cancer 274 SLLFSLFEAUrinary Bladder Cancer, AML, NHL 275 YLVYILNEL CLL, Melanoma, NHL 276ALFTFSPLTV Uterine Cancer 277 LLPPLESLATVCLL, BRCA, Urinary Bladder Cancer, HNSCC 278 QLLDVVLTI HNSCC 280VLPDPEVLEAV Gallbladder Cancer and Bile Duct Cancer, NHL, SCLC 281ILRESTEEL Melanoma 282 LLADVVPTT CLL, Uterine Cancer, AML, NHL, HNSCC283 ALYIGDGYVIHLA Esophageal Cancer, Urinary Bladder Cancer, UterineCancer, NHL 284 ILLSQTTGV CLL, Urinary Bladder Cancer, AML, HNSCC 285QLLHVGVTV CLL, Melanoma, Urinary Bladder Cancer, AML, NHL 286 YLFPGIPELNSCLC, CLL, Melanoma, AML, NHL, HNSCC 289 VLLEIEDLQV CLL, NHL 290GLLDLNNAILQL Uterine Cancer 292 LLWEAGSEA Melanoma 293 GLGELQELYLAML, NHL 294 ILDPFQYQLMelanoma, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 297VLADIELAQA CLL 298 VMITKLVEV Gallbladder Cancer and Bile Duct Cancer 300ALLGQTFSL AML, HNSCC 301 FLVEDLVDSLCLL, BRCA, Melanoma, Uterine Cancer, AML 302 ALLQEGEVYSAMelanoma, Urinary Bladder Cancer 303 AILPQLFMV Melanoma 304 MTLGQIYYLNSCLC, SCLC, CRC, HCC, BRCA, Melanoma,Urinary Bladder Cancer, Uterine Cancer, GallbladderCancer and Bile Duct Cancer, AML, HNSCC 306 ALVNVQIPLMelanoma, Uterine Cancer 307 ALPVSLPQICLL, BRCA, Melanoma, AML, NHL, HNSCC 308 SQYSGQLHEV CLL 309 GLFDGVPTTASCLC, Urinary Bladder Cancer, Gallbladder Cancerand Bile Duct Cancer, HNSCC 310 FLVDTPLARAGallbladder Cancer and Bile Duct Cancer, HNSCC 311 RLYTGMHTVSCLC, BRCA, NHL, HNSCC 312 IISDLTIALNSCLC, CRC, BRCA, Melanoma, EsophagealCancer, Uterine Cancer, Gallbladder Cancer and BileDuct Cancer, NHL, HNSCC 314 ALIAEGIALV Uterine Cancer 317 SLAALVVHVNSCLC, Gallbladder Cancer and Bile Duct Cancer, HNSCC 318 GLINTGVLSVSCLC, CLL, NHL, HNSCC 319 SLEPQIQPVHCC, CLL, BRCA, Melanoma, Gallbladder Cancerand Bile Duct Cancer, AML, HNSCC 320 KMFEFVEPLLSCLC, Brain Cancer, BRCA, Melanoma, UrinaryBladder Cancer, Uterine Cancer, Gallbladder Cancerand Bile Duct Cancer, AML, HNSCC 321 GLFEDVTQPGILL CLL 322 TLMTSLPALCLL, BRCA, Melanoma, Uterine Cancer, GallbladderCancer and Bile Duct Cancer, AML, NHL 323 IQIGEETVITV CRC, CLL, BRCA 324FLYDEIEAEV CLL 325 FIMPATVADATAVCLL, BRCA, Melanoma, Uterine Cancer, NHL 326 FLPEALDFV CLL, AML, NHL 327GLAPFTEGISFV NSCLC, Gallbladder Cancer and Bile Duct Cancer 328ALNDQVFEI AML 330 QLALKVEGV CLL, Urinary Bladder Cancer, AML, NHL, HNSCC331 KVDTVWVNV CLL, Gallbladder Cancer and Bile Duct Cancer, HNSCC 332YLISELEAA RCC, GC, BRCA, Melanoma 333 FLPDANSSV HCC, Melanoma 334TLTKVLVAL CLL 335 YSLSSVVTV HNSCC 336 ILLTAIVQV Melanoma 337HLLSELEAAPYL CLL 338 SVLEDPVHAV BRCA, Esophageal Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL 339 GLWEIENNPTVGallbladder Cancer and Bile Duct Cancer KA 340 ALLSMTFPL SCLC, AML 341SQIALNEKLVNL Urinary Bladder Cancer 342 HIYDKVMTVEsophageal Cancer, Gallbladder Cancer and Bile Duct Cancer 343SLLEVNEESTV CLL 345 VIWKALIHL NSCLC, Melanoma, NHL 346 LLDSKVPSV HNSCC347 SLFKHDPAAWEA Uterine Cancer, HNSCC 348 ILLDVKTRLMelanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC 350ALLDVTHSELTV BRCA, HNSCC 351 SLIPNLRNV CRC, Esophageal Cancer 352SLLELLHIYV CLL, AML 354 LILEGVDTVBRCA, Urinary Bladder Cancer, Uterine Cancer, NHL 356 KLLGKLPELMelanoma, Urinary Bladder Cancer 358 ALDEYTSEL Urinary Bladder Cancer359 YLLPESVDL CLL, Uterine Cancer, NHL, HNSCC 360 ALDJGASLLHL HNSCC 361ALYELEGTTV NSCLC, SCLC, CLL, BRCA, Urinary Bladder Cancer,Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC 362TLYGLSVLL AML 363 KVLDVSDLESV NSCLC, Esophageal Cancer, Urinary BladderCancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC 364 LLQNEQFELUrinary Bladder Cancer, Uterine Cancer, GallbladderCancer and Bile Duct Cancer 365 YVIDQGETDVYVCLL, Urinary Bladder Cancer, NHL 366 RLLDMGETDLMLCLL, Urinary Bladder Cancer, AML, NHL 367 SLQNHNHQLNSCLC, CRC, Melanoma, Esophageal Cancer, AML, NHL, HNSCC 370 SLLQDLVSVBRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC 372TMLLNIPLV CLL, Gallbladder Cancer and Bile Duct Cancer, AML, NHL 374FLLQQHLISA CLL 375 SLTETIEGV Gallbladder Cancer and Bile Duct Cancer 376AMFESSQNVLL CLL 379 IMEGTLTRVRCC, CLL, Melanoma, Urinary Bladder Cancer, NHL 380 TLIEDEIATISCLC, Melanoma, Uterine Cancer, GallbladderCancer and Bile Duct Cancer, AML, HNSCC 381 FIDEAYVEVGC, CLL, Melanoma, NHL 382 ALQNYIKEA BRCA 384 ILFANPNIFVCLL, Urinary Bladder Cancer, Uterine Cancer, NHL 385 SLLEQGLVEABRCA, AML, HNSCC 386 ILFRYPLTI Melanoma, Uterine Cancer, AML 387ALFQATAEV SCLC, Melanoma, Urinary Bladder Cancer, UterineCancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC 388SLTIDGIRYV Brain Cancer 389 LLADVTHLL Melanoma, AML 393 GLLDTQTSQVLCRC, Gallbladder Cancer and Bile Duct Cancer, TA HNSCC 394 LLAVIGGLVYLBRCA 395 ALALGGIAVV CLL, NHL, HNSCC 396 ALLPDLPALSCLC, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC 397YLFGERLLEC CLL, Uterine Cancer 398 KLLEEDGTIITLBRCA, Esophageal Cancer, Gallbladder Cancer and Bile Duct Cancer 400SLLTEQDLWTV CLL 401 ILLDDTGLAYICLL, Urinary Bladder Cancer, Gallbladder Cancerand Bile Duct Cancer, NHL 403 KLYDRILRV BRCA 407 YLMDLINFL AML 408VLDDSIYLV CLL, Uterine Cancer, NHL 409 LLDAMNYHL CLL, NHL 411 LLAHLSPELMelanoma 412 YLDDLNEGVYI BRCA 413 TLLEKVEGC Melanoma 414 YVDDIFLRVGC, Melanoma 415 LLDKVYSSVBrain Cancer, CLL, BRCA, Urinary Bladder Cancer,Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC416 VLSDIIQNLSV CLL, NHL 417 NLQDTEYNL CLL, AML, NHL 418 ALAELENIEVCLL, BRCA, Urinary Bladder Cancer, GallbladderCancer and Bile Duct Cancer, HNSCC 419 GQYEGKVSSV BRCA 420 FMYDTPQEVGallbladder Cancer and Bile Duct Cancer 422 FLPKLLLLA Melanoma 423GLDGPPPTV NHL 424 TLLDALYEIMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC 425FLYEKSSQV SCLC 426 RLADKSVLV BRCA, AML 427 ALLPLSPYLGallbladder Cancer and Bile Duct Cancer 428 KLGHTDILVGVCLL, Uterine Cancer, HNSCC 429 GLVNDLARVSCLC, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, NHL 430HLYSSIEHLTT SCLC, BRCA, Urinary Bladder Cancer, NHL 431 SLVNVVPKLCLL, BRCA, Urinary Bladder Cancer, GallbladderCancer and Bile Duct Cancer, AML, NHL 433 AMLNEPWAVBRCA, Melanoma, Urinary Bladder Cancer, HNSCC 434 KVSNSGITRVEsophageal Cancer, HNSCC 435 WLMPVIPALMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML 436 HLAEVSAEVNSCLC, SCLC, CLL, BRCA, Melanoma, UrinaryBladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC438 KLLPLAGLYL CLL, BRCA, Melanoma, Uterine Cancer, GallbladderCancer and Bile Duct Cancer, AML, HNSCC 439 YLLQEIYGI AML 440 ALADGVTMQVSCLC, BRCA, Melanoma, Uterine Cancer 441 ALLENPKMELUrinary Bladder Cancer 443 GLWEIENNPTVGallbladder Cancer and Bile Duct Cancer 444 GLLRDEALAEVCLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, AML, NHL, HNSCC 445GLYQDPVTL Uterine Cancer, AML 446 QLIPALAKV Brain Cancer 447 QLVPALAKVBRCA, Melanoma, HNSCC 448 NLLETKLQL CLL, Melanoma, NHL, HNSCC 450FMIDASVHPTL CLL, Urinary Bladder Cancer, HNSCC 451 LLLLDTVTMQVMelanoma, HNSCC 452 ILLEHGADPNL CLL, Urinary Bladder Cancer, NHL 453KLLEATSAV SCLC, BRCA, Uterine Cancer, Gallbladder Cancerand Bile Duct Cancer, AML, NHL, HNSCC 454 KLPPPPPQA BRCA, AML, HNSCC 455SLLKEPQKVQL CLL, Melanoma, HNSCC 456 LLIGHLERV BRCA, AML, NHL, HNSCC 458SLIDKLYNI SCLC, Brain Cancer, Melanoma, Urinary BladderCancer, AML, HNSCC 459 ALITEVVRL SCLC, CLL, AML, NHL 461 VMFRTPLASVBRCA, Urinary Bladder Cancer, Uterine Cancer, NHL 462 KLAKQPETV NHL 463SLVESHLSDQL CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, TLGallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 464 ALNDCIYSV HNSCC465 QLCDLNAEL SCLC, Melanoma, AML, HNSCC 466 VLIANLEKLUrinary Bladder Cancer, NHL 467 FLAKDFNFLNSCLC, Melanoma, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 468 YLRSVGDGETVUterine Cancer 469 YLASDEITTV CLL 470 MLQDSIHVV BRCA 472 KLLEVSDDPQVHNSCC 473 AMATESILHFA AML 474 YLDPALELGPR BRCA NV 476 ALMERTGYSMVUterine Cancer 477 ALLPASGQIALCLL, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC 478YLLHEKLNL NHL 479 SLFGNSGILENV Melanoma, Uterine Cancer, AML, HNSCC 480ALLEDSCHYL HNSCC 481 GLIEDYEALL Melanoma, AML 482 SLAPAGIADAMelanoma, Uterine Cancer, HNSCC 483 ALTDIVSQVNSCLC, SCLC, BRCA, Uterine Cancer, GallbladderCancer and Bile Duct Cancer, HNSCC 484 SLIEKVTQLSCLC, CRC, CLL, BRCA, Melanoma, EsophagealCancer, Urinary Bladder Cancer, Uterine Cancer, AML, NHL 486 AVMESIQGVCLL 487 LLINSVFHV Urinary Bladder Cancer, NHL 488 FLAEDPKVTLCLL, BRCA, Melanoma, Urinary Bladder Cancer, NHL 489 KMWEELPEVVCLL, Esophageal Cancer, Urinary Bladder Cancer, AML, NHL, HNSCC 490FLLQHVQEL CLL, NHL 491 GLNDRSDAV BRCA, AML, HNSCC 492 SLFDGFADGLGV BRCA493 GLLGEKTQDLI CLL, Melanoma, Urinary Bladder Cancer, Uterine GVCancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC 495 FIFSEKPVFVMelanoma, AML, NHL 496 FLVEKQPPQV CLL, NHL 497 GLLEKLTAISCLC, CLL, BRCA, Melanoma, Urinary Bladder Cancer, AML, NHL 498KLWTGGLDNTV NSCLC, Brain Cancer, CLL, Urinary Bladder Cancer,Uterine Cancer, NHL 500 SLMEDQVLQL CLL, AML 501 LLDPNVKSIFVBRCA, Urinary Bladder Cancer, HNSCC 502 RLLAQVPGLMelanoma, Uterine Cancer, Gallbladder Cancer andBile Duct Cancer, AML, NHL 503 SLNHFTHSVHCC, CLL, Urinary Bladder Cancer, AML, NHL, HNSCC 504 GLSDGNPSLCLL, Uterine Cancer 505 SLAPGDVVRQV BRCA, Urinary Bladder Cancer, HNSCC506 KLLGKVETA CLL, NHL 507 KLIDDQDISISL CLL, Urinary Bladder Cancer, NHL508 ILAQEQLVVGV SCLC, Gallbladder Cancer and Bile Duct Cancer 509FLFDTKPLIV CLL 510 KLYSVVSQL NHL 511 FLDPYCSASV SCLC, Uterine Cancer 512SLSEIVPCL Uterine Cancer, AML, HNSCC 513 SLWPSPEQLMelanoma, AML, NHL, HNSCC 514 ILVDWLVQVBRCA, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC 517LLMPIPEGLTL Urinary Bladder Cancer, Uterine Cancer, HNSCC 518 KLNAEVACVBRCA, Melanoma, Urinary Bladder Cancer, Uterine Cancer, HNSCC 519GLLHLTLLL SCLC, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC 520LAVHPSGVAL SCLC, CLL, BRCA, Gallbladder Cancer and Bile Duct Cancer 521MLLTKLPTI Brain Cancer, CLL, Uterine Cancer, AML, NHL, HNSCC 522TLWYRSPEV Melanoma 523 YQIPRTFTL CLL, AML 524 ALIENLTHQICLL, Melanoma, NHL 525 VLLEAGEGLVTINSCLC, SCLC, CLL, Urinary Bladder Cancer, Uterine Cancer, NHL, HNSCC 526RLAEVGQYEQV Uterine Cancer, NHL 528 SVAEGRALMSVNSCLC, CLL, BRCA, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, HNSCC 529 LLADELITVSCLC, CLL, HNSCC 530 VMYADIGGMDICLL, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, HNSCC 531 YTLPIASSIRL BRCA 532ALNNLLHSL Melanoma, Esophageal Cancer, Urinary BladderCancer, Uterine Cancer, Gallbladder Cancer and BileDuct Cancer, AML, NHL 533 RMVAEIQNV CLL, NHL 534 HLANIVERL CLL 535KLIAQNLEL AML, NHL, HNSCC 536 YLVEGRFSV CLL, Urinary Bladder Cancer 538LLLAHIIAL BRCA, Urinary Bladder Cancer, Uterine Cancer 539 ALFDAQAQVMelanoma, AML 540 ALIPETTTLTV NHL 541 SMLEPVPELGallbladder Cancer and Bile Duct Cancer 542 RVWDISTVSSV NSCLC, CLL, BRCA543 GLLPTPITQQASL BRCA 544 LLWDVPAPSL CLL, Uterine Cancer, HNSCC 545LLADLLHNV BRCA 546 VMIAGKVAVV SCLC, Urinary Bladder Cancer, HNSCC 547TLDITPHTV Esophageal Cancer 548 ALWENPESGEL BRCA 549 AMLENASDIKLSCLC, CLL, Urinary Bladder Cancer 550 FLYDEIEAEVNL CLL 551 KLYESLLPFACLL, BRCA, Urinary Bladder Cancer, GallbladderCancer and Bile Duct Cancer, AML, NHL, HNSCC 552 GLLDLPFRVGVCLL, AML, NHL 553 SLLNQDLHWSL CLL 554 LLMPSSEDLLL CLL, Melanoma, HNSCC555 YVLEGLKSV CRC, CLL, Esophageal Cancer, Urinary BladderCancer, Uterine Cancer, NHL, HNSCC 556 FLTDLEDLTLCLL, Uterine Cancer, NHL 557 KLYDDMIRL Brain Cancer, NHL 558 GLLENIPRVCLL, BRCA, Melanoma, AML, NHL 559 VTVPPGPSL CLL, AML 560 ALWDIETGQQTCLL, Urinary Bladder Cancer, Uterine Cancer, TTGallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 561 YLQLTQSELCLL, NHL, HNSCC 563 WLLPYNGVTV CLL, Uterine Cancer, NHL 565 ALQETPTSVBRCA, Gallbladder Cancer and Bile Duct Cancer 566 VIADGGIQNVCRC, CLL, BRCA, Urinary Bladder Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL 567 SLLPLDDIVRV CLL, BRCA568 TLYDIAHTPGV CLL, Urinary Bladder Cancer, NHL, HNSCC 570 ALANQIPTVHCC 571 LLLTTIPQI Melanoma 572 ALADLIEKELSV CLL, NHL 573 ILVANAIVGVCLL, SCLC, Urinary Bladder Cancer 575 YLISQVEGHQVNSCLC, SCLC, BRCA, Urinary Bladder Cancer, HNSCC 577 VMFEDGVLMRLSCLC, CLL, Urinary Bladder Cancer, AML, NHL, HNSCC 578 FLDPGGPMMKLSCLC, CLL, BRCA, Urinary Bladder Cancer, HNSCC 579 NLMEMVAQLSCLC, CLL, Melanoma, Urinary Bladder Cancer, NHL 580 LLMENAERVCLL, Esophageal Cancer, Urinary Bladder Cancer,Uterine Cancer, NHL, HNSCC 581 RLWNETVEL AML, NHL 582 TLCDVILMV Melanoma583 ILANDGVLLAA CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC 585 ALWDLAADKQTLMelanoma 586 KLKPGDLVGV Uterine Cancer 587 VMNDRLYAI CLL, NHL 588SLLPLSHLV CLL, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC589 KLYPQLPAEI CLL, BRCA, Urinary Bladder Cancer 590 SLIEKLWQTUterine Cancer, AML 591 SMAELDIKL AML, HNSCC 594 IMLKGDNITLUterine Cancer 595 VLLSIYPRVCLL, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer 596ALLDQTKTLAE CLL, NHL SAL 597 KLLEGQVIQLCLL, Melanoma, Gallbladder Cancer and Bile Duct Cancer, AML 598FLFPHSVLV CRC 599 YLLNDASLISV SCLC 600 ALAAPDIVPALCLL, Uterine Cancer, AML 601 SAFPFPVTVCLL, Gallbladder Cancer and Bile Duct Cancer, AML 603 FLIEPEHVNTV CLL604 SILDRDDIFV CLL, Melanoma, NHL 605 KLYEAVPQLGallbladder Cancer and Bile Duct Cancer, HNSCC 607 RLYSGISGLELCLL, Melanoma, AML, NHL 609 ALWKQLLELCRC, Esophageal Cancer, Uterine Cancer 611 YLLDDGTLVV Uterine Cancer 612YLYNEGLSV BRCA, Urinary Bladder Cancer, AML, NHL, HNSCC 613 RLLPPGAVVAVCLL, BRCA, Urinary Bladder Cancer, GallbladderCancer and Bile Duct Cancer, HNSCC 614 LLLPDQPPYHL CLL 615 VLPPDTDPAMelanoma, Esophageal Cancer 616 VLIDEVESLCRC, Uterine Cancer, Gallbladder Cancer and BileDuct Cancer, AML, NHL, HNSCC 619 ALQDRVPLABRCA, Gallbladder Cancer and Bile Duct Cancer 620 KLLNKIYEA BRCA, AML621 VLMDRLPSLL CLL 622 RLLGEEVVRVL Urinary Bladder Cancer, AML, NHL QA623 YLVEDIQHI NSCLC, PC 624 FLQEEPGQLLCLL, Urinary Bladder Cancer, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, NHL 625 VVLEGASLETVCLL, Urinary Bladder Cancer 626 LLMATILHL CLL, AML, NHL, HNSCC 627KLLETELLQEI CLL, Urinary Bladder Cancer 628 KLWEFFQVDV Melanoma 629HLLNESPML RCC, PC, BRCA, Melanoma, Uterine Cancer,Gallbladder Cancer and Bile Duct Cancer, AML 630 LLSHVIVALCLL, Gallbladder Cancer and Bile Duct Cancer, NHL 631 FLDVFLPRVSCLC, CLL, NHL 632 YLIPDIDLKL CLL, AML, NHL, HNSCC 633 ALSRVSVNV CLL 634VVAEFVPLI CLL, AML, NHL 635 SLDSTLHAVSCLC, Melanoma, Urinary Bladder Cancer, UterineCancer, Gallbladder Cancer and Bile Duct Cancer 636 LLTEIRAVV CLL, NHL637 SIYGGFLLGV Urinary Bladder Cancer, Gallbladder Cancer and BileDuct Cancer, HNSCC 638 KLIQESPTVGallbladder Cancer and Bile Duct Cancer, AML 639 SLFQNCFELCLL, Melanoma, Uterine Cancer, NHL, HNSCC NSCLC = non-small cell lungcancer, SCLC = small cell lung cancer, RCC = kidney cancer,CRC = colonor rectum cancer, GC = stomach cancer, HCC = liver cancer, PC= pancreatic cancer, PrC = prostate cancer, BRCA = breast cancer, NHL= non-Hodgkin lymphoma,AML = acute myeloid leukemia, CLL = chroniclymphocytic leukemia, HNSCC = head and neck squamous cell carcinoma.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 1, 11, 17, 27, 45, 57, 58, 61, 62, 65, 72, 74, 79, 84,97, 98, 104, 105, 125, 126, 143, 150, 157, 161, 167, 176, 179, 183, 184,195, 198, 201, 204, 213, 217, 222, 228, 234, 248, 263, 264, 268, 285,287, 303, 313, 319, 323, 333, 335, 338, 343, 347, 348, 355, 356, 359,373, 385, 394, 395, 403, 415, 421, 427, 428, 429, 430, 431, 434, 441,443, 444, 446, 447, 450, 454, 456, 457, 458, 459, 463, 474, 477, 479,480, 486, 489, 492, 493, 497, 501, 503, 506, 514, 517, 521, 526, 538,539, 540, 541, 545, 554, 558, 568, 573, 576, 578, 579, 589, 595, 597,599, 602, 607, 610, 613, 616, 627, 632, 635, and 637 for the—in onepreferred embodiment combined—treatment of NSCLC.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No 1, 6, 17, 19, 20, 27, 28, 31, 34, 36, 38, 45, 47, 48,51, 54, 55, 56, 57, 58, 59, 60, 61, 65, 66, 72, 75, 76, 79, 82, 85, 88,91, 92, 98, 103, 108, 117, 123, 125, 126, 127, 135, 141, 142, 149, 152,153, 166, 167, 169, 171, 176, 183, 184, 200, 205, 213, 214, 216, 228,233, 234, 237, 240, 242, 248, 249, 251, 256, 263, 264, 277, 279, 283,286, 288, 296, 300, 301, 312, 314, 315, 322, 323, 328, 331, 338, 341,344, 345, 346, 366, 372, 373, 385, 388, 394, 399, 401, 404, 410, 418,420, 421, 427, 428, 431, 433, 435, 437, 439, 441, 443, 444, 446, 449,450, 451, 454, 461, 463, 469, 473, 474, 475, 479, 481, 492, 493, 500,501, 514, 517, 521, 522, 523, 530, 531, 539, 541, 542, 545, 551, 552,554, 555, 556, 558, 560, 561, 563, 565, 568, 574, 575, 581, 589, 590,592, 595, 597, 602, 606, 610, 613, 616, 618, 622, 625, 626, 627, 628,629, 632, 637, 638, and 640 for the—in one preferred embodimentcombined—treatment of SCLC.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No 1, 2, 6, 19, 26, 27, 57, 58, 61, 63, 64, 65, 69, 77,79, 85, 95, 97, 98, 103, 107, 121, 125, 126, 127, 128, 129, 143, 148,150, 155, 157, 166, 170, 174, 177, 200, 201, 204, 207, 213, 217, 222,223, 229, 234, 235, 242, 243, 252, 258, 264, 267, 271, 275, 279, 285,287, 294, 303, 306, 311, 313, 317, 319, 323, 328, 330, 332, 333, 336,346, 347, 348, 354, 355, 356, 359, 360, 361, 375, 382, 385, 387, 393,395, 405, 410, 415, 424, 430, 431, 441, 444, 447, 450, 459, 461, 465,466, 472, 477, 480, 486, 491, 492, 497, 498, 499, 501, 505, 506, 508,513, 514, 518, 528, 533, 539, 541, 542, 543, 554, 560, 561, 565, 568,575, 576, 583, 588, 589, 591, 592, 594, 601, 610, 616, 619, 624, 629,631, 633, 635, and 640 for the—in one preferred embodimentcombined—treatment of esophageal cancer.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 6, 48, 68, 106, 118, 127, 135, 143, 157, 174, 209,247, 279, 292, 300, 313, 28, 332, 333, 340, 357, 358, 385, 389, 410,425, 431, 450, 456, 464, 473, 474, 492, 501, 506, 514, 523, 528, 538,539, 541, 558, 586, 589, 590, 592, 593, 606, 610, 619, 620, 628, and 635for the—in one preferred embodiment combined—treatment of brain cancer.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No 6, 7, 17, 27, 56, 59, 61, 65, 76, 93, 103, 110, 131,141, 143, 149, 169, 204, 212, 216, 226, 228, 229, 230, 242, 255, 264,266, 268, 271, 273, 283, 284, 285, 286, 287, 288, 289, 303, 309, 331,333, 335, 336, 340, 358, 362, 371, 372, 373, 375, 393, 395, 396, 401,420, 422, 423, 427, 439, 446, 459, 466, 504, 521, 539, 554, 576, 580,592, 595, 597, 610, 616, 635, 637, and 640 for the—in one preferredembodiment combined—treatment of breast cancer (BrCa).

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 6, 20, 139, 283, 373, 396, 418, 430, 441, 446, 472,473, 474, 479, 501, 575, 578, 589, 627, and 640 for the—in one preferredembodiment combined—treatment of MCC.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 7, 9, 97, 98, 183, 217, 218, 222, 234, 235, 237, 240,241, 242, 263, 268, 271, 275, 285, 303, 311, 313, 360, 364, 394, 403,410, 424, 431, 450, 455, 497, 502, 514, 558, 564, 595, 608, 610, and 616for the—in one preferred embodiment combined—treatment of RCC.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 7, 24, 27, 64, 65, 84, 87, 95, 97, 125, 126, 127, 130,137, 143, 183, 200, 272, 275, 291, 292, 311, 312, 332, 335, 346, 351,357, 358, 364, 372, 398, 405, 407, 410, 421, 423, 427, 443, 459, 464,499, 539, 540, 603, 609, 630, 631, and 632 for the—in one preferredembodiment combined—treatment of pancreatic cancer (PC).

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 9, 31, 58, 183, 275, 335, 410, 421, 499, 514, 564,616, and 640 for the—in one preferred embodiment combined—treatment ofgastric cancer (GC).

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 9, 14, 19, 20, 28, 32, 36, 48, 54, 57, 58, 63, 64, 66,87, 92, 94, 97, 98, 108, 125, 129, 139, 143, 144, 154, 157, 159, 163,166, 167, 170, 174, 176, 178, 188, 197, 198, 201, 204, 207, 208, 209,212, 213, 214, 217, 222, 229, 234, 237, 248, 256, 267, 269, 271, 273,275, 286, 290, 294, 301, 306, 309, 313, 327, 328, 332, 338, 339, 340,341, 346, 347, 349, 355, 359, 360, 367, 369, 370, 371, 372, 378, 383,385, 387, 393, 394, 395, 396, 401, 406, 409, 410, 411, 415, 419, 420,423, 427, 428, 429, 430, 432, 441, 443, 447, 450, 451, 452, 457, 463,464, 465, 472, 473, 474, 476, 477, 479, 480, 484, 486, 489, 492, 498,501, 513, 514, 517, 521, 523, 526, 528, 531, 538, 539, 540, 541, 546,551, 554, 558, 560, 564, 573, 575, 576, 579, 583, 586, 589, 597, 599,603, 606, 610, 611, 613, 617, 627, 628, 632, 635, 637, 638, and 640 forthe—in one preferred embodiment combined—treatment of hepatocellularcarcinoma (HCC).

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 9, 10, 14, 19, 24, 28, 79, 87, 101, 144, 148, 149,153, 169, 174, 190, 210, 212, 216, 222, 223, 242, 252, 257, 271, 288,298, 299, 303, 310, 311, 317, 331, 333, 334, 346, 347, 348, 360, 367,386, 390, 393, 394, 395, 423, 477, 479, 483, 486, 494, 495, 502, 514,521, 527, 529, 539, 554, 585, 610, 616, 626, 632, and 640 for the—in onepreferred embodiment combined—treatment of urinary bladder cancer.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 19, 22, 26, 28, 31, 33, 34, 36, 38, 47, 48, 49, 57,58, 59, 60, 65, 74, 79, 80, 92, 98, 119, 126, 128, 129, 132, 144, 149,159, 161, 166, 183, 204, 214, 237, 242, 248, 251, 252, 253, 256, 262,263, 270, 271, 272, 275, 276, 277, 280, 282, 284, 285, 287, 289, 296,299, 301, 308, 309, 319, 321, 323, 324, 325, 331, 333, 343, 355, 358,365, 366, 373, 374, 379, 381, 384, 391, 394, 395, 397, 400, 401, 404,408, 409, 410, 412, 415, 428, 448, 450, 451, 452, 457, 459, 468, 475,480, 486, 488, 489, 490, 496, 503, 504, 506, 507, 508, 510, 520, 523,529, 533, 536, 542, 544, 550, 552, 556, 558, 559, 561, 566, 567, 571,572, 573, 576, 577, 579, 580, 587, 589, 591, 595, 596, 600, 601, 603,604, 610, 624, 630, 631, 632, 634, and 639 for the—in one preferredembodiment combined—treatment of leukemia.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 19, 22, 31, 34, 38, 48, 57, 58, 61, 62, 63, 64, 74,77, 92, 97, 98, 101, 105, 107, 143, 144, 150, 155, 167, 176, 177, 183,184, 199, 213, 217, 222, 230, 248, 251, 256, 264, 277, 282, 283, 287,291, 309, 314, 316, 321, 323, 329, 331, 338, 339, 343, 344, 355, 365,366, 373, 384, 388, 391, 394, 395, 401, 410, 412, 431, 443, 444, 450,452, 457, 461, 463, 468, 472, 474, 487, 496, 499, 501, 514, 517, 521,523, 525, 530, 540, 542, 544, 549, 550, 551, 552, 555, 560, 563, 564,565, 566, 568, 572, 573, 575, 576, 578, 580, 584, 588, 589, 596, 599,603, 611, 614, 616, 618, 621, 622, 624, 625, 626, 627, 631, 632, and 633for the—in one preferred embodiment combined—treatment of melanoma.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 19, 22, 24, 58, 76, 79, 84, 86, 97, 98, 126, 176, 178,188, 222, 243, 285, 300, 301, 303, 311, 318, 319, 320, 342, 348, 349,355, 356, 359, 376, 384, 395, 397, 398, 421, 426, 428, 430, 441, 444,448, 449, 450, 456, 458, 459, 473, 478, 480, 510, 514, 518, 521, 528,531, 535, 541, 545, 546, 554, 557, 568, 575, 576, 577, 578, 579, 580,581, 597, 599, 610, 619, 622, 627, 632, 635, and 640 for the—in onepreferred embodiment combined—treatment of colorectal cancer (CRC).

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 34, 51, 84, 174, 178, 200, 207, 212, 216, 237, 252,264, 288, 323, 332, 333, 372, 394, 395, 410, 443, 446, 447, 486, 492,501, 518, 539, 551, 554, 606, 610, 637, and 640 for the—in one preferredembodiment combined—treatment of prostate cancer (PrC)

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 47, 51, 54, 58, 64, 84, 87, 125, 200, 213, 228, 235,237, 323, 335, 346, 385, 423, 473, 501, 526, 539, 554, 558, 561, 610,626, and 640 for the—in one preferred embodiment combined—treatment ofgallbladder cancer.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 47, 51, 54, 58, 64, 84, 87, 125, 200, 213, 228, 235,237, 323, 335, 346, 385, 423, 473, 501, 526, 539, 554, 558, 561, 610,626, and 640 for the—in one preferred embodiment combined—treatment ofbile duct cancer.

Thus, another aspect of the present invention relates to the use of atleast one peptide according to the present invention according to anyone of SEQ ID No. 48, 126, 127, 129, 149, 153, 157, 207, 214, 228, 235,237, 288, 323, 328, 332, 358, 360, 385, 395, 423, 427, 446, 497, 514,539, 558, 565, 599, 619, 632, 637, and 640 for the—in one preferredembodiment combined—treatment of uterine cancer.

Then, another aspect of the present invention relates to the use of thepeptides according to the present invention for the—preferablycombined—treatment of a proliferative disease selected from the group ofovarian cancer, non-small cell lung cancer, small cell lung cancer,kidney cancer, brain cancer, colon or rectum cancer, stomach cancer,liver cancer, pancreatic cancer, prostate cancer, leukemia, breastcancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinarybladder cancer, uterine cancer, gallbladder cancer, bile duct cancer.

The present invention furthermore relates to peptides according to thepresent invention that have the ability to bind to a molecule of thehuman major histocompatibility complex (MHC) class-I or—in an elongatedform, such as a length-variant—MHC class-II.

The present invention further relates to the peptides according to thepresent invention wherein said peptides (each) consist or consistessentially of an amino acid sequence according to SEQ ID NO: 1 to SEQID NO: 640.

The present invention further relates to the peptides according to thepresent invention, wherein said peptide is modified and/or includesnon-peptide bonds.

The present invention further relates to the peptides according to thepresent invention, wherein said peptide is part of a fusion protein, inparticular fused to the N-terminal amino acids of the HLA-DRantigen-associated invariant chain (li), or fused to (or into thesequence of) an antibody, such as, for example, an antibody that isspecific for dendritic cells.

The present invention further relates to a nucleic acid, encoding thepeptides according to the present invention. The present inventionfurther relates to the nucleic acid according to the present inventionthat is DNA, cDNA, PNA, RNA or combinations thereof.

The present invention further relates to an expression vector capable ofexpressing and/or expressing a nucleic acid according to the presentinvention.

The present invention further relates to a peptide according to thepresent invention, a nucleic acid according to the present invention oran expression vector according to the present invention for use in thetreatment of diseases and in medicine, in particular in the treatment ofcancer.

The present invention further relates to antibodies that are specificagainst the peptides according to the present invention or complexes ofsaid peptides according to the present invention with MHC, and methodsof making these.

The present invention further relates to T-cell receptors (TCRs), inparticular soluble TCR (sTCRs) and cloned TCRs engineered intoautologous or allogeneic T cells, and methods of making these, as wellas NK cells or other cells bearing said TCR or cross-reacting with saidTCRs.

The antibodies and TCRs are additional embodiments of theimmunotherapeutic use of the peptides according to the invention athand.

The present invention further relates to a host cell comprising anucleic acid according to the present invention or an expression vectoras described before. The present invention further relates to the hostcell according to the present invention that is an antigen presentingcell, and preferably is a dendritic cell.

The present invention further relates to a method for producing apeptide according to the present invention, said method comprisingculturing the host cell according to the present invention, andisolating the peptide from said host cell or its culture medium.

The present invention further relates to said method according to thepresent invention, wherein the antigen is loaded onto class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellor artificial antigen-presenting cell by contacting a sufficient amountof the antigen with an antigen-presenting cell.

The present invention further relates to the method according to thepresent invention, wherein the antigen-presenting cell comprises anexpression vector capable of expressing or expressing said peptidecontaining SEQ ID No. 1 to SEQ ID No.: 640, preferably containing SEQ IDNo. 1 to SEQ ID No. 259, or a variant amino acid sequence.

The present invention further relates to activated T cells, produced bythe method according to the present invention, wherein said T cellselectively recognizes a cell which expresses a polypeptide comprisingan amino acid sequence according to the present invention.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence according to the present invention,the method comprising administering to the patient an effective numberof T cells as produced according to the present invention.

The present invention further relates to the use of any peptide asdescribed, the nucleic acid according to the present invention, theexpression vector according to the present invention, the cell accordingto the present invention, the activated T lymphocyte, the T cellreceptor or the antibody or other peptide- and/or peptide-MHC-bindingmolecules according to the present invention as a medicament or in themanufacture of a medicament. Preferably, said medicament is activeagainst cancer.

Preferably, said medicament is a cellular therapy, a vaccine or aprotein based on a soluble TCR or antibody.

The present invention further relates to a use according to the presentinvention, wherein said cancer cells are ovarian cancer, non-small celllung cancer, small cell lung cancer, kidney cancer, brain cancer, colonor rectum cancer, stomach cancer, liver cancer, pancreatic cancer,prostate cancer, leukemia, breast cancer, Merkel cell carcinoma,melanoma, esophageal cancer, urinary bladder cancer, uterine cancer,gallbladder cancer, bile duct cancer, and preferably ovarian cancercells.

The present invention further relates to biomarkers based on thepeptides according to the present invention, herein called “targets”,that can be used in the diagnosis of cancer, preferably ovarian cancer.The marker can be over-presentation of the peptide(s) themselves, orover-expression of the corresponding gene(s). The markers may also beused to predict the probability of success of a treatment, preferably animmunotherapy, and most preferred an immunotherapy targeting the sametarget that is identified by the biomarker. For example, an antibody orsoluble TCR can be used to stain sections of the tumor to detect thepresence of a peptide of interest in complex with MHC.

Optionally the antibody carries a further effector function such as animmune stimulating domain or toxin.

The present invention also relates to the use of these novel targets inthe context of cancer treatment.

ABCA1 has been shown to be hyper-methylated in ovarian and prostatecancer cell lines. ABCA1 methylation was linked with poor prognosis inovarian cancer patients (Lee et al., 2013a; Chou et al., 2015). In coloncancer, over-expression of ABCA1 resulted in a decrease of cellularcholesterol and inhibition of tumor growth. This growth inhibition couldbe due to apoptosis since over-expression of ABCA1 enhanced cytochrome crelease from mitochondria (Smith and Land, 2012).

ABCB8 is associated with drug resistance in human melanomas (Chen etal., 2009b).

ABCC1 is up-regulated in primary breast cancer, lung and esophagealcancers, leukemia and childhood neuroblastoma (Cole et al., 1992; Burgeret al., 1994; Norris et al., 1996; Nooter et al., 1997). Scientists haveidentified ABCC1 as a direct transcriptional target of Notch1 signalingin an etoposide-resistant variant of the MCF7 breast cancer cell line(Cho et al., 2011). Several publications have demonstrated thatincreased ABCC1 expression in cancers was linked with loss of functionalp53 (Fukushima et al., 1999; Sullivan et al., 2000).

ABCC10 was shown to be associated with paclitaxel and gemcitabineresistance in breast cancer, gemcitabine resistance in the non-smallcell lung cancer cell line A549 and vinorelbine resistance in thenon-small cell lung cancer cell lines SK-LC6 and NCI-H23 (Ikeda et al.,2011; Bessho et al., 2009; Dorman et al., 2015). ABCC10 was shown to beassociated with breast cancer pathogenesis (Domanitskaya et al., 2014).ABCC10 was shown to be up-regulated in pancreatic ductal adenocarcinoma,hepatocellular carcinoma, non-small cell lung cancer, chroniclymphocytic leukemia and pediatric acute myeloid leukemia(Mohelnikova-Duchonova et al., 2013b; Borel et al., 2012; Steinbach etal., 2006; Wang et al., 2009c; Hoellein et al., 2010). ABCC10 expressionwas shown to be correlated with tumor grade in colorectal cancer andpathological grades and TNM stages in adenocarcinoma of the lung(Hlavata et al., 2012; Wang et al., 2009c).

Elevated levels of ABCC4 were present in human NK/T-cell lymphoma cells,lung cancer cells and gastric cancer cells. Moreover, copy numbervariation in the ABCC4 gene has been associated with the risk ofesophageal squamous cell carcinoma (Sun et al., 2014b; Zhao et al.,2014b; Zhang et al., 2015d; Zhang et al., 2015n). Furthermore, silencingof ABCC4 expression in drug-resistant gastric cancer cells resulted inan increase in apoptosis and cell cycle arrest in the G1 phase. Anothergroup has shown that knockdown of ABCC4 inhibited gastric cancer cellgrowth and blocked cell cycle progression (Chen et al., 2014d; Zhang etal., 2015d).

Down-regulation of ABCD1 expression was observed in renal cellcarcinoma, colorectal cancers and melanoma tumorigenesis (Heimerl etal., 2007; Galamb et al., 2009; Hour et al., 2009).

ABCF1 was up-regulated in post-treatment tumors compared withnon-neoplastic tissues (Hlavac et al., 2013). Moreover, repressing ABCF1expression by miR-23a over-expression or siABCF1 resulted in recovery of5-fluorouracil sensitivity in microsatellite unstable colorectal cancercells (Li et al., 2015c).

Several publications have shown elevated levels of AB11 in various typesof cancer such as epithelial ovarian cancer, colorectal carcinoma,breast cancer and hepatocellular carcinoma (Wang et al., 2007a; Liu etal., 2009a; Steinestel et al., 2013; Steinestel et al., 2014; Zhang etal., 2015f). In epithelial ovarian cancer, over-expression of AB11 wassignificantly associated with advanced stage, high grade and elevatedCa-125 level (Zhang et al., 2015f). Knockdown of AB11 resulted indecreased invasiveness and migration ability in breast cancer celllines. Similarly, silencing of AB11 gene in leukemic cells led toimpaired cell migration and abnormal actin remodeling (Wang et al.,2007a; Yu et al., 2008).

ABL2 was over-expressed in non-small cell lung cancers, anaplasticthyroid cancers, melanoma, colorectal, pancreatic cancers,hepatocellular carcinomas, ovarian serous cystadenocarcinoma, lungadenocarcinoma and lung squamous cell carcinoma (Gil-Henn et al., 2013;Greuber et al., 2013; Xing et al., 2014). In highly invasive breastcancer cell lines, ABL2 regulates proliferation, survival, and invasiondown-stream of de-regulated EGFR, Her2, IGFR and Src kinases (Srinivasanand Plattner, 2006; Srinivasan et al., 2008).

ADCK3 expression was shown to be altered in colorectal cancer (Hennig etal., 2012).

ADCY5 encodes adenylate cyclase 5, a membrane-bound adenylyl cyclaseenzyme that mediates G protein-coupled receptor signaling through thesynthesis of the second messenger cAMP (RefSeq, 2002). ADCY5 genehyper-methylation and reduced mRNA expression occurs in acutelymphoblastic leukemia, chronic lymphocytic leukemia and lungadenocarcinoma (Kuang et al., 2008; Tong et al., 2010; Sato et al.,2013).

The expression of ADCY6 was shown to be differentially regulated inlaryngeal squamous cell carcinoma (Colombo et al., 2009).

AGL has been shown to be a tumor suppressor in bladder cancer. Loss ofAGL in cancer cells induces tumor growth both in vitro and in vivothrough increased glycine synthesis via induction of the glycinesynthesizing enzyme serine hydroxymethyltransferase 2 (Guin et al.,2014; Ritterson et al., 2015).

AHCY down-regulation contributes to tumorigenesis (Leal et al., 2008).AHCY can promote apoptosis. It inhibits migration and adhesion ofesophageal squamous cell carcinoma cells suggesting a role incarcinogenesis of the esophagus (Li et al., 2014c). AHCY proteinexpression is up-regulated in colon cancer (Kim et al., 2009a; Watanabeet al., 2008; Fan et al., 2011). AHCY might be a potential biomarker inovarian cancer (Peters et al., 2005).

Recent work has identified a mutation in the AKAP6 gene in gastriccancer (Li et al., 2016).

ALDH5A1 has been reported to be over-expressed in breast ductalcarcinoma in situ. In addition, inhibitors of ALDH5A1 such as disulfiramand valproic acid were able to inhibit net proliferation of a breastductal carcinoma models (Kaur et al., 2012).

It has been observed that a patient suffering from Alström syndrome dueto mutations in the ALMS1 gene developed also papillary thyroidcarcinoma. Another study identified ALMS1 as a tumor neo-antigen inchronic lymphocytic leukemia (Rajasagi et al., 2014; Papadakis et al.,2015).

ALS2CR12 was shown to be associated with cutaneous basal cell carcinomasusceptibility (Stacey et al., 2015). An intronic single nucleotidepolymorphism in ALS2CR12 was shown to be associated with breast cancerrisk (Lin et al., 2015b).

In oral squamous cell carcinomas (OSCC) up-regulation of ALYREF mRNA andprotein level is linked to regional lymph node metastasis caused bycellular invasiveness and migration (Saito et al., 2013). ALYREF mRNA isover-expressed in a wide variety of tumor tissues, whereas the proteinlevel is poorly detected in high-grade cancers (Dominguez-Sanchez etal., 2011). ALYREF is a target of nuclear PI3K signaling, whichregulates its sub-nuclear residency, cell proliferation and mRNA exportactivities through nuclear Akt phosphorylation and phosphoinositideassociation (Okada et al., 2008).

ANKRD26 belongs to a gene family that was shown to be highly expressedin cancer patients with poor outcome (Sahab et al., 2010). ANKRD26 wasshown to be associated with the putative tumor suppressor RARRES1 (Sahabet al., 2010).

Homozygous deletion of the AP1B1 gene was found to be inactive insporadic meningioma. These findings imply that AP1B1 gene could play animportant role in meningioma development (Peyrard et al., 1994; Sayagueset al., 2007).

APOBEC3G is associated with liver metastasis of colorectal cancer,hepatocellular carcinoma and lymphomas (Nowarski et al., 2012; Chang etal., 2014b; Weidle et al., 2015). APOBEC3G is associated with poorprognosis in colon carcinoma with hepatic metastasis and with reducedoverall survival in diffuse large B-cell lymphoma (Lan et al., 2014;Jais et al., 2008).

APOL2 was shown to be over-expressed in ovarian/peritoneal carcinoma(Davidson et al., 2011).

Over-expression of AQP5 has been linked to many kinds of cancers such ascolorectal, cervical, lung, breast and epithelial ovarian cancer (Shanet al., 2014; Yan et al., 2014a). In non-small cell lung cancer elevatedAQP5 expression levels were associated with lymph node metastasis.Furthermore, the expression levels of AQP5 in stage III and IV tumorswere significantly higher compared with stage I and II tumors (Song etal., 2015a). Previous studies have revealed that AQP5 can activate theRAS/ERK/RB pathway in rectal cancer cells and enhance the incidence andprogression of cancer (Woo et al., 2008; Kang et al., 2008b).

AR has been implicated in the development of various cancers such asprostate, castrate-resistant prostate, breast, glioblastoma multiforme,colon and gastric (Wang et al., 2009d; Yu et al., 2015b; Mehta et al.,2015; Wang et al., 2015a; Sukocheva et al., 2015). In addition topromoting prostate cancer proliferation, androgen signaling through ARleads to apoptosis via inducing the expression of p21 (WAF1/CIP1), acyclin-dependent kinase inhibitor (Yeh et al., 2000).

A study has shown down-regulation of ARFGEF1 in breast cancer celllines. Another group reported ARFGEF1 to be a tumor suppressor in breastcancer patients (Pongor et al., 2015; Kim et al., 2011a). It ispostulated that microRNA-27b mediated up-regulation of ARFGEF1 promotestumor growth by activating the ARFGEF1/Akt pathway (Matsuyama et al.,2016).

ARHGAP26 was shown to be down-regulated in acute myeloid leukemia andduring the progression of CML (Qian et al., 2010; Aly and Ghazy, 2014).ARHGAP26 is associated with metastatic brain tumors from primary lungadenocarcinoma (Zohrabian et al., 2007). ARHGAP26 is associated withrisk and tumor size of uterine leiomyoma, increased CML risk and is afavorable prognostic marker for AML (Dzikiewicz-Krawczyk et al., 2014;Aissani et al., 2015).

ARHGEF19 was shown to be associated with metastasis of hepatocellularcarcinoma (Zhou et al., 2014a). ARHGEF19 was described as a part of theplanar cell polarity/non-canonical Wnt pathway, a pathway associatedwith cancer (Miller et al., 2011).

ARID5B was shown to be dysregulated in prostate cancer (Davalieva etal., 2015). ARID5B was shown to be associated with susceptibility,relapse hazard and poorer treatment outcome in childhood acutelymphoblastic leukemia (Xu et al., 2012; Evans et al., 2014). ARID5B wasshown to be a potential target regulated by SALL4, a transcriptionfactor which is associated with acute myeloid leukemia (Milanovich etal., 2015). ARID5B was shown to be a target of the oncogenic TEAD4protein in gastric cancer (Lim et al., 2014). ARID5B was shown to befrequently mutated in endometrioid tumors (Kandoth et al., 2013). ARID5Bmight play a role in cervical cancer development through its function asa human papillomavirus 16 integration site (Matovina et al., 2009).ARID5B was shown to be up-regulated in the highly metastatic adenoidcystic carcinoma cell line ACC-M of human salivary glands, may beinvolved in adenoid cystic carcinoma lung metastasis and might serve asa diagnostic marker and therapeutic target (Sun et al., 2004a).

ARL6IP1 is associated with cervical cancer cell growth and invasion (Guoet al., 2010).

ASUN was shown to be up-regulated in testicular seminomas and an ovariancarcinoma cell line (Bourdon et al., 2002). A study has shown that ATF6Bwas essential for lysophosphatidic acid-induced YAP dephosphorylation inhuman epithelial ovarian cancer cell lines (Cai and Xu, 2013).

ATM is a tumor suppressor which is frequently mutated in a broad rangeof human cancers including lung, colorectal, breast and hematopoieticcancers (Weber and Ryan, 2014). Loss of ATM has been associated with theincreased risk of various cancers including, breast, colorectal,prostate, lung and pancreatic ductal adenocarcinoma (Swift et al., 1987;Geoffroy-Perez et al., 2001; Angele et al., 2004; Roberts et al., 2012;Grant et al., 2013; Russell et al., 2015). Studies have shown that IL-8was able to rescue cell migration and invasion defects in ATM-depletedcells (Chen et al., 2015d). Low level of ATM protein was correlated withpoor metastasis-free survival in breast cancer patients. In addition,miR-203 and miR-421 over-expression may be involved in ATM de-regulationin these patients (Bueno et al., 2014; Rondeau et al., 2015).

ATP10A is associated with relapse and decrease of event-free survival inB-cell precursor acute lymphatic leukemia (Olsson et al., 2014).

ATP2A2 is associated with skin cancer, colon cancer and lung cancer(Korosec et al., 2006; Hovnanian, 2007).

The expression of ATP2A3 is markedly decreased in colon, stomach, lungand breast cancer and ATP2A3 expression is induced when these cellsundergo differentiation in vitro (Gelebart et al., 2002; Arbabian etal., 2013; Papp et al., 2012). In colon cancer, the expression of ATP2A3has been shown to be negatively regulated by the APC/beta-catenin/TCF4oncogenic pathway (Brouland et al., 2005). In addition, ATP2A3expression was found to be negatively related with lymphatic invasion(Gou et al., 2014).

Researchers have shown that patients with a variety of malignancies suchas melanoma, non-small cell lung carcinoma and chronic myelogenousleukemia develop high-titer IgG antibodies against ATP6AP1 followingvaccination with irradiated, autologous GM-CSF secreting tumor cells orallogeneic bone marrow transplantation. Another report has detectedelevated levels of ATP6AP1 in invasive ductal and lobular carcinoma aswell as breast cancer. Furthermore, mutations in the ATP6AP1 gene werefound in follicular lymphoma (Hodi et al., 2002; Anderson et al., 2011;Okosun et al., 2016).

ATP6V1H was shown to interact with the tumor associated gene TM9SF4 inthe colon cancer cell lines HCT116 and SW480 (Lozupone et al., 2015).ATP6V1H, as part of the V-ATPase V1 sector, was shown to be associatedwith invasive behavior of colon cancer cells and tumor pH gradient(Lozupone et al., 2015).

Elevated levels of intracellular ATP8A1 protein diminished theinhibitory role of miR-140-3p in the growth and mobility ofnon-small-cell lung cancer cells (Dong et al., 2015).

ATR encodes ATR serine/threonine kinase, which belongs to thePI3/P14-kinase family. This kinase has been shown to phosphorylatecheckpoint kinase CHK1, checkpoint proteins RAD17, and RAD9, as well astumor suppressor protein BRCA1 (RefSeq, 2002). Copy number gain,amplification, or translocations of the ATR gene were observed in oralsquamous cell carcinoma cell lines (Parikh et al., 2014). It has beendemonstrated that truncating ATR mutations in endometrial cancers areassociated with reduced disease-free and overall survival (Zighelboim etal., 2009). VE-822, an ATR inhibitor was shown to radiosensitize andchemosensitize pancreatic cancer cells in vitro and pancreatic tumorxenografts in vivo (Fokas et al., 2012; Benada and Macurek, 2015).

AURKA is over-expressed in many tumors arising from breast, colon,ovary, skin and other tissues, and it has been shown to function as anoncogene when exogenously expressed in numerous cell line models(Nikonova et al., 2013).

AURKB expression is up-regulated in different cancer types, includinglung, colorectal and breast cancer as well as leukemia and therebyassociated with poor prognosis. So development of AURKB inhibitors forclinical therapy is an interesting field (Hayama et al., 2007; Pohl etal., 2011; Hegyi et al., 2012; Goldenson and Crispino, 2015). AURKBover-expression leads to phosphorylation of histone H3 and to chromosomeinstability, a crucial factor for carcinogenesis (Ota et al., 2002;Tatsuka et al., 1998). AURKB activity augments the oncogenicRas-mediated cell transformation (Kanda et al., 2005).

Over-expression and gene amplification of AURKC was detected in prostateand breast cancer cell lines as well as in colorectal cancers, thyroidcarcinoma and cervical cancer. Others have observed an increase of AURKCprotein in seminomas, implying that it might play a role in theprogression of testicular cancers. In addition, AURKC has been shown tobe oncogenic since its over-expression transforms NIH 3T3 cells intotumors (Baldini et al., 2010; Tsou et al., 2011; Khan et al., 2011;Zekri et al., 2012). In colorectal cancer, the expression of AURKC wascorrelated with the grade of disease and tumor size (Hosseini et al.,2015). Furthermore, over-expression of AURKC induces an increase in theproliferation, transformation and migration of cancer cells (Tsou etal., 2011).

Heterozygous carriers of BBS1 gene seem to be at increased risk ofdeveloping clear cell renal cell carcinoma (Beales et al., 2000).Furthermore, BBS1 was recognized by serum antibodies of melanomapatients but not by healthy controls (Hartmann et al., 2005). It wasreported that malignant pleural mesothelioma patients with high BBS1expression had an increased median overall survival of 16.5 versus 8.7months compared to those that showed low BBS1 expression (Vavougios etal., 2015).

BBX expression was shown to be associated with the NF-kB/Snail/YY1/RKIPcircuitry gene expression, which is associated with metastatic prostatecancer and non-Hodgkin's lymphoma (Zaravinos et al., 2014).

BCL2L13 was shown to be over-expressed in solid and blood cancers,including glioblastoma and acute lymphoblastic leukemia (Jensen et al.,2014; Yang et al., 2010).

BCL2L13 is associated with an unfavorable clinical outcome in childhoodacute lymphoblastic leukemia (Holleman et al., 2006).

Quantitative PCR and immunohistochemistry analysis revealed that BDH1was up-regulated in high-grade prostate cancer. Moreover, the BDH1 genewas frequently amplified in metastatic conjunctival melanomas (Lake etal., 2011; Saraon et al., 2013).

BHLHE41 is associated with breast cancer metastasis, endometrial cancermetastasis, triple-negative breast cancer metastasis, pancreatic cancer,human squamous carcinoma and lung cancer (Sato et al., 2012a; Piccolo etal., 2013; Liao et al., 2014a; Takeda et al., 2014; Falvella et al.,2008; Adam et al., 2009). BHLHE41 is associated with CDDP resistance inhuman oral cancer (Wu et al., 2012e).

BOLA2 was described as a novel candidate target gene of the c-Myconcogene which may be associated with malignant hepatocytetransformation by altering cell cycle control (Hunecke et al., 2012).

BOP1 is associated with ovarian cancer and colorectal cancer(Wrzeszczynski et al., 2011; Killian et al., 2006). BOP1 was shown to bea target gene of Wnt-catenin which induced EMT, cell migration andexperimental metastasis of colorectal cancer cells in mice. Thus, BOP1may serve as a therapeutic target in the treatment of colorectal cancermetastasis (Qi et al., 2015). BOP1 is associated with hepatocellularcarcinoma invasiveness and metastasis (Chung et al., 2011). BOP1 wasdescribed as a member of a molecular pathway associated with cell cyclearrest in a gastric cancer cell line upon treatment with mycophenolicacid, indicating a potential association of BOP1 with the anticanceractivity of the drug (Dun et al., 2013a; Dun et al., 2013b). BOP1 may bea possible marker for rectal cancer (Lips et al., 2008). BOP1 wasdescribed as a potential oncogene in ovarian cancer (Wrzeszczynski etal., 2011). BOP1 was shown to be up-regulated in hepatocellularcarcinoma (Chung et al., 2011). BOP1 was shown to be associated withmicrovascular invasion, shorter disease-free survival and metastasis inhepatocellular carcinoma (Chung et al., 2011). BOP1 was described as asubunit of the PeBoW complex, which is essential for cell proliferationand maturation of the large ribosomal subunit. Over-expression of BOP1was shown to inhibit cell proliferation (Rohrmoser et al., 2007).Expression of an amino-terminally truncated form of BOP1 resulted indown-regulation of G(1)-specific Cdk2 and Cdk4 kinase complexes,retinoblastoma and cyclin A while Cdk inhibitors p21 and p27 wereup-regulated. This led to an arrest in the G(1) phase (Pestov et al.,2001).

BUB1B is a tumor inhibitory protein. BUB1B regulates the spindleassembly checkpoint. BUB1B is inactivated or down-regulated in tumors.Mutations in BUB1B are also linked to tumor development (Aylon and Oren,2011; Fagin, 2002; Malumbres and Barbacid, 2007; Rao et al., 2009).BUB1B is associated with gastric carcinogenesis through oncogenicactivation (Resende et al., 2010). BUB1B mutation is one of the causesfor colorectal cancer (Karess et al., 2013; Grady, 2004).

C10orf137 is associated with squamous cell lung cancer and colorectalcancer (Gylfe et al., 2010; Zheng et al., 2013).

Over-expression of C1R has been found in the saliva of oral squamouscell carcinoma patients. On the other hand, inactivation of C1R wasobserved in paclitaxel-based treatment in hypopharynx cancer patients(Xu et al., 2013a; Kawahara et al., 2016).

C2CD3 was shown to be associated with oropharyngeal squamous cellcarcinomas (Wang et al., 2013g).

C4orf46 was shown to be down-regulated in renal cell carcinoma andC4orf46 expression was shown to be negatively correlated with theFuhrman grade in clear cell renal cell carcinoma (Yu et al., 2014).

Increased expression of CA8 has previously been shown in squamous cellcarcinomas, adenocarcinomas, adenosquamous cell carcinomas andcolorectal carcinoma (Akisawa et al., 2003). Over-expression of CA8 hasbeen shown to induce apoptosis in lung carcinoma A549 and humanembryonic kidney HEK293 cells. Furthermore, it inhibits cellproliferation in melanoma, prostate, liver and bladder cancer cells (Liuet al., 2002a). siRNA-mediated knockdown of CA8 revealed significantinhibition in cell proliferation and colony formation of a colon cancercell line HCT116 (Nishikata et al., 2007).

CAAP1 was shown to be associated with drug resistance in cancers(Wijdeven et al., 2015).

CAMSAP1 was shown to be associated with outcome in pediatric acutelymphoblastic leukemia and prognosis of laryngeal squamous cellcarcinoma (Sun et al., 2014a; Wang et al., 2015c). CAMSAP1 was shown tobe up-regulated in laryngeal squamous cell carcinoma (Sun et al.,2014a).

CAND1 is associated with prostate cancer and lung cancer (Zhai et al.,2014; Salon et al., 2007).

Recent studies have shown that CANX was over-expressed in lung cancerpatients compared to healthy controls. These findings imply that CANXcould be used as a diagnostic marker for lung cancer (Kobayashi et al.,2015b). CANX was down-regulated in HT-29 cells and MCF-7 human breastadenocarcinoma cells growing as colonies compared to monolayers (Yeatesand Powis, 1997).

Polymorphisms in the CARS gene have been linked to the development ofbreast cancer in the Chinese population. Moreover, CARS showedsignificantly higher association with different molecular networks inglioblastoma multiforme (He et al., 2014; Kim et al., 2012c).

CCAR1 is associated with medulloblastoma, small cell prostate carcinoma,colon carcinoma and non-Hodgkin's Lymphoma (Bish and Vogel, 2014; Leviet al., 2011; Scott et al., 2014; Ou et al., 2009). CCAR1 was shown tobe down-regulated in breast cancer (Zhang et al., 2007).

CCDC110 was shown to interact with the high-risk human papillomavirus 18E6 oncogene in a yeast two-hybrid system and thus may be a potentialoncogenic target for cancer biotherapy (Li et al., 2008b). CCDC110 wasdescribed as a cancer-testis antigen associated with multiple myelomawhich could potentially be used to vaccinate patients (Condomines etal., 2007). CCDC110 was shown to be a novel cancer-testis antigen whichelicited humoral immune responses in patients with various types ofcancer. Thus, CCDC110 might be a target for cancer immunotherapy (Monjiet al., 2004).

CCNA1 encodes cyclin A1, which belongs to the highly conserved cyclinfamily involved in the regulation of CDK kinases (RefSeq, 2002).Elevated levels of CCNA1 were detected in epithelial ovarian cancer,lymphoblastic leukemic cell lines as well as in childhood acutelymphoblastic leukemia patients. Others have observed over-expression ofCCNA1 protein and mRNA in prostate cancer and in tumor tissues ofanaplastic thyroid carcinoma patients (Holm et al., 2006; Wegiel et al.,2008; Marlow et al., 2012; Arsenic et al., 2015). Recent studies haveshown that silencing of CCNA1 in highly cyclin A1 expressing ML1leukemic cells slowed S phase entry, decreased proliferation andinhibited colony formation (Ji et al., 2005).

Over-expression of CCNA2 inhibits the proliferation of hepatocellularcarcinoma cells. Over-expression of CCNA2 in endometrial adenocarcinomacells decreases cell growth and increases apoptosis. CCNA2 expression inmelanoma cells reduces tumor growth and metastasis and concomitantlyincreases apoptosis in tumors (Lau, 2011). CCNA2 can promote cancer cellproliferation, invasion, adhesion, differentiation, survival andmetastasis. It plays an important role in angiogenesis and extracellularmatrix production.

CCNA2 promotes tumor growth and increases tumor vascularization whenover-expressed in gastric adenocarcinoma cells. Silencing of CCNA2expression decreases tumor growth in pancreatic cancer cells. CCNA2 canpromote the proliferation of prostate cancer cells (Lau, 2011; Chen andDu, 2007). CCNA2 over-expression induces epithelial-mesenchymaltransition, leading to laryngeal tumor invasion and metastasis (Liu etal., 2015e). CCNA2 is dysregulated in colorectal cancer (Chang et al.,2014a). CCNA2 is over-expressed in prostate cancer, gliomas, pancreaticcancer, and breast cancer. CCNA2 is associated with increasedaggressiveness, vascularization, and estrogen independence in breastcancer, suggesting a major role of CCNA2 in breast cancer progression(Zuo et al., 2010).

CCNB2 is up-regulated in colorectal adenocarcinoma (Park et al., 2007).CCNB2 is over-expressed in various human tumors. Strong CCNB2 expressionin tumor cells is associated with a poor prognosis in patients withadenocarcinoma of lung and invasive breast carcinoma (Takashima et al.,2014; Albulescu, 2013).

A CCNB3-BCOR gene fusion was shown to be associated with the cancerentity of undifferentiated small round cell sarcomas (Haidar et al.,2015). CCNB3-BCOR (Ewing-like) sarcomas located in the axial skeletonand soft tissues were shown to be associated with shorter survivalcompared to Ewing sarcomas (Puls et al., 2014). CCNB3 was shown tointeract with cdk2, a protein involved in cell cycle transition (Nguyenet al., 2002).

Over-expression and amplification of CCNE1 was observed in various typesof cancer, including breast, colon, gastric, lung, endometrialintraepithelial carcinoma, uterine serous carcinoma and high gradeserous ovarian cancer (Donnellan and Chetty, 1999; Kuhn et al., 2014;Noske et al., 2015). In addition, increased expression of CCNE1 is auseful marker of poor prognosis in lung cancer (Huang et al., 2012). Astudy has shown that CCNE1 is down-regulated by both miR-497 andmiR-34a, which synergistically retard the growth of human lung cancercells (Han et al., 2015b).

Studies have shown that acute myeloid leukemia patients with long-termin vitro proliferation of AML cells showed altered expression in CCNF(Hatfield et al., 2014). Furthermore, low CCNF expression was related topoor overall survival and recurrence-free survival in hepatocellularcarcinoma patients (Fu et al., 2013a).

CCR4 has been described as a prognostic marker in various tumors such asrenal cell carcinoma, head and neck squamous cell carcinoma, gastriccancer, breast cancer, colon cancer and Hodgkin lymphoma (Ishida et al.,2006; Olkhanud et al., 2009; Yang et al., 2011; Tsujikawa et al., 2013;Al-haidari et al., 2013; Liu et al., 2014d). Studies have revealed thatgastric cancer patients with CCR4-positive tumors had significantlypoorer prognosis compared to those with CCR4-negative tumors (Lee etal., 2009).

CCT4 deregulation causes esophageal squamous cell carcinoma and lungadenocarcinoma (Wang et al., 2015i; Tano et al., 2010). CCT4 isupregulated in gastric cancers (Malta-Vacas et al., 2009).

CCT5 is associated with breast cancer (Campone et al., 2008). CCT5 wasshown to be up-regulated in sinonasal adenocarcinoma (Tripodi et al.,2009). CCT5 is associated with overall survival in small cell lungcancer, drug resistance in gastric carcinoma and breast cancer and lymphnode metastasis in esophageal squamous cell carcinoma (Niu et al., 2012;Ooe et al., 2007; Uchikado et al., 2006; Ludwig et al., 2002).

CCT8 was shown to be up-regulated in hepatocellular carcinoma (Huang etal., 2014b). CCT8 is associated with histologic grades, tumor size andpoor prognosis of hepatocellular carcinoma (Huang et al., 2014b).

Strong CD68 expression was found in basal cell carcinoma, fibrolamellarcarcinomas, Hodgkin lymphoma, human glioma, squamous cell carcinoma,adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma,papillary adenocarcinoma, metastatic adenocarcinoma, bronchioloalveolarcarcinoma as well as in induced rat tumors (Strojnik et al., 2006;Strojnik et al., 2009; Ross et al., 2011; Glaser et al., 2011; Yoon etal., 2012; Banat et al., 2015). In breast cancer, increased CD68expression was correlated with larger tumor size, higher TNM stages andHer-2 positivity. Moreover, the number of CD68 cells was positivelycorrelated with the expression of Ras (Li et al., 2015b).

CD74 expression has been observed in various cancers, includinggastrointestinal, renal, non-small cell lung, glioblastoma cell lines,thymic epithelial neoplasms and head and neck squamous cell carcinomas(Ioachim et al., 1996; Datta et al., 2000; Young et al., 2001; Ishigamiet al., 2001; Kitange et al., 2010; Gold et al., 2010; Kindt et al.,2014). Preclinical studies in B-cell lymphoma and multiple myelomarevealed that CD74 could be used as a therapeutic target for thesedisorders (Burton et al., 2004).

Over-expression of CDC123 was observed in a choriocarcinoma cell line.Other studies have detected CDC123 protein in basal breast cancer(Adelaide et al., 2007; Kobayashi et al., 2013).

CDC6 expression is de-regulated in different cancer types includinggallbladder, cervical and prostate cancer (Wu et al., 2009; Wang et al.,2009e; Robles et al., 2002; Shu et al., 2012). CDC6 co-operates withc-Myc to promote genetic instability, tumor-like transformation andapoptosis attenuation (Chen et al., 2014a). Hypoxia-induced ATR promotesthe degradation of CDC6. Initiation of DNA replication is regulated byp53 through Cdc6 protein stability (Duursma and Agami, 2005; Martin etal., 2012).

Several publications have reported over-expression of CDCl₇ in manyhuman tumors, including ovarian cancer, colorectal cancer, melanoma,diffuse large B-cell lymphoma, oral squamous cell carcinoma and breastcancer (Clarke et al., 2009; Kulkarni et al., 2009; Choschzick et al.,2010; Hou et al., 2012; Cheng et al., 2013a; Chen et al., 2013b).Elevated levels of CDCl₇ protein predicts disease-free survival inpatients suffering from ovarian cancer (Kulkarni et al., 2009).

Elevated levels of CDH2 have been reported in patients suffering fromgastric, breast, prostate, bladder, malignant bone and soft tissuetumors (Rieger-Christ et al., 2001; Chan et al., 2001; Jaggi et al.,2006; Nagi et al., 2005; Niimi et al., 2013). In colorectal cancer,over-expression of CDH2 correlated with local infiltration depth, tumorstaging, vascular invasion and tumor differentiation level (Ye et al.,2015).

CDK1 is over-expressed in different cancer types including breast,gastric, liver and colorectal cancer and is associated with tumorprogression and poor prognosis (Kim et al., 1999; Sung et al., 2014;Masuda et al., 2003; Kim, 2007; Ito et al., 2000; Chae et al., 2011).CDK1 regulates via phosphorylation HIF-1 alpha, Bcl-2 proteins, Sp1 andp53 and thereby influences tumor growth, apoptosis and DNA damageresponse (Nantajit et al., 2010; Zhang et al., 2011; Chuang et al.,2012; Sakurikar et al., 2012; Warfel et al., 2013).

CDK12 mutations were identified in a variety of tumors, includingovarian, breast, prostate, and intestinal tumors (Vrabel et al., 2014).

CDK13 is associated with pancreatic cancer and skin cancer (Ansari etal., 2015; Nelson et al., 1999; Chandramouli et al., 2007). CDK13 isamplified in hepatocellular carcinoma (Kim et al., 2012a).

Over-expression of CDK4 has been observed in many tumor types, such asoral squamous cell carcinoma, pancreatic endocrine tumors, lung cancerand nasopharyngeal carcinoma (Dobashi et al., 2004; Wikman et al., 2005;Lindberg et al., 2007; Poomsawat et al., 2010; Jiang et al., 2014c).Researchers have noted that patients suffering from nasopharyngealcarcinoma with higher levels of CDK4 expression had poorer survivalrates compared to those with lower levels of CDK4 expression (Liu etal., 2014j).

CDK5 is over-expressed in many tumors including prostate cancer,pancreatic cancer, lung cancer, glioblastoma and breast cancer (Strocket al., 2006; Liu et al., 2008b; Feldmann et al., 2010; Demelash et al.,2012; Liang et al., 2013). Inhibition of CDK5 kinase activity using aCDK5 dominant-negative mutant or the drug roscovitine significantlydecreased the migration and invasion of pancreatic cancer cells in vitro(Eggers et al., 2011; Pozo et al., 2013).

CDK6 has been shown to regulate the activity of tumor suppressor proteinRb. CDK6 can exert its tumor-promoting function by enhancingproliferation and stimulating angiogenesis (Kollmann et al., 2013). Thepharmacological inhibition of CDK6 was shown to inhibit the growthdifferentiation of abnormal leukemic cells (Placke et al., 2014).

Over-expression of CELSR2 was found in head and neck squamous cellcarcinoma samples, whereas in breast cancer CELSR2 was down-regulated(Lin et al., 2004; Huang et al., 2005a).

CENPN may be a prognostic marker for early breast cancer (Li et al.,2013d).

CEP55 is strongly up-regulated in human gastric cancer (Tao et al.,2014b). Fibulin-5 increases the activity of CEP55 resulting in apromotion of cell metastasis in nasopharyngeal carcinoma (Hwang et al.,2013). CEP55 may regulate nasopharyngeal carcinoma via theosteopontin/CD44 pathway (Chen et al., 2012a). CEP55 is over-expressedin oropharyngeal squamous cell carcinoma (Janus et al., 2011). CEP55 wasidentified as novel target in lung cancer (Lai et al., 2010). CEP55 canbe detected in colon cancer and breast cancer (Colak et al., 2013; Inodaet al., 2009; Inoda et al., 2011 b; Inoda et al., 2011a; Castle et al.,2014). Down-regulation of CEP55 inhibits cell motility and invasion inovarian cancer (Zhang et al., 2015m). CEP55 is significantlyup-regulated in ovarian cancer cell lines and lesions compared to normalcells and adjacent non-cancerous ovarian tissue (Zhang et al., 2015m).CEP55 is classified as an oncogene and its dys-regulation affects thecell cycle pathway. This may play a role in laryngeal squamous cellcarcinoma progression (Hui et al., 2015). CEP55 over-expressionsignificantly correlates with tumor stage, aggressiveness, metastasisand poor prognosis across multiple tumor types (Jeffery et al., 2015b;Chen et al., 2009a; Janus et al., 2011). The complex of CEP55 withAurora-A may enhance the progression and metastasis of head and neckcancer (Chen et al., 2015a; Waseem et al., 2010). An extract ofGraptopetalum paraguayense can down-regulate the expression level ofCEP55 in hepatocellular carcinoma (Hsu et al., 2015). CEP55 isover-expressed in bladder cancer and prostate cancer (Singh et al.,2015; Shiraishi et al., 2011). CEP55 mRNA is significantly higherexpressed in muscle-invasive bladder cancer compared tonon-muscle-invasive bladder cancer. However, there is no difference inprotein expression (Singh et al., 2015).

It was reported that CEP57 is up-regulated in a subset of primaryprostate adenocarcinomas, whereas deletion in CEP57 gene was detected inbreast carcinoma (Gentile et al., 2001; Sinha et al., 2011; Cuevas etal., 2013). Moreover, alterations of CEP57 were linked with poorprognosis in patients suffering from breast cancer with early age ofonset. On the other hand, in prostate cancer elevated levels of CEP57were not correlated with poor patient survival but instead with amoderate yet significant BCR-free survival advantage (Sinha et al.,2011; Mang et al., 2015). It has been postulated that CEP57 maycontribute to apoptosis by modulating the activity or function of Bcl-2in breast cancer (Zhao et al., 2005).

CEP97 is associated with breast cancer (Rappa et al., 2014).

CERS1 is down-regulated in in nilotinib-resistant chronic myeloidleukemia cells (Camgoz et al., 2013). CERS1 generated C(18)-ceramidelevels are significantly decreased in head and neck squamous cellcarcinoma (HNSCC) tumors. Decreased C(18)-ceramide levels in HNSCC tumortissues are significantly associated with the higher incidences oflymphovascular invasion, and pathologic nodal metastasis (Karahatay etal., 2007). CERS1 generated C(18)-ceramide mediates cell death in cancercells (Saddoughi and Ogretmen, 2013).

CERS2 was shown to be down-regulated in meningioma (Ke et al., 2014b).CERS2 was shown to be up-regulated in colorectal cancer, lung squamouscell carcinoma and breast cancer (Moriya et al., 2012; Chen et al.,2015c; Schiffmann et al., 2009). CERS2 is associated with metastasis anddrug-resistance of breast cancer, growth, invasion and metastasis ofprostate cancer, diverse proliferation, metastasis and invasion ofbladder cancer and hepatocellular carcinoma (Tang et al., 2010; Zhao etal., 2013a; Perez et al., 2014; Xu et al., 2014a; Zi et al., 2015).CERS2 may be a potential biomarker for colorectal cancer, meningioma andbladder cancer (Zhao et al., 2013a; Ke et al., 2014b; Chen et al.,2015c).

Studies have shown that the expression of CFB was reduced in sera ofpatients suffering from nasopharyngeal carcinoma. On the other hand, theexpression of CFB was more than two times higher in plasma samples frompancreatic ductal adenocarcinoma patients compared with plasma fromhealthy individuals. Others have observed an association of the CFBlocus with melanoma (Budowle et al., 1982; Seriramalu et al., 2010; Leeet al., 2014a).

CHCHD7 is associated with pleomorphic adenoma (Matsuyama et al., 2011).

CHD7 is associated with cutaneous T-cell lymphoma, CpG island methylatorphenotype 1 colorectal carcinoma, gastric cancer with microsatelliteinstability and small-cell lung cancer (Kim et al., 2011b; Tahara etal., 2014; Litvinov et al., 2014b; Pleasance et al., 2010). CHD7 wasshown to be up-regulated in colon cancer (Scanlan et al., 2002). CHD7 isassociated with survival outcomes of pancreatic cancer (Colbert et al.,2014).

A report has postulated that polymorphisms in the CHST1 gene couldaccount for 5-fluorouracil-induced toxicity in colorectal cancerpatients. Another study found that LN229 glioblastoma cells expresselevated levels of CHST1 (Hayatsu et al., 2008; Rumiato et al., 2013;Arbitrio et al., 2016).

CKLF was shown to be up-regulated in high-grade glioma (Yang et al.,2013).

CLDN16 was shown to be up-regulated in papillary thyroid carcinomas andovarian cancer (Rangel et al., 2003; Fluge et al., 2006). CLDN16expression was shown to be associated aggressiveness, high mortality andpoor prognosis in breast cancer (Martin et al., 2008; Martin and Jiang,2011). CLDN16 was shown to be associated with kidney cancer (Men et al.,2015). CLDN16 was described as a potential biomarker for breast cancer(Kuo et al., 2010).

CLSPN is up-regulated in non-small cell lung carcinoma (NSCLC).Over-expression of CLSPN is associated with a bad prognosis in NSCLC(Allera-Moreau et al., 2012).

Over-expression of CLSTN3 has been found in testicular cancer as well ashuman embryonal carcinoma (Dormeyer et al., 2008).

Single-nucleotide polymorphisms (SNPs) in the CNOT1 gene were detectedin osteosarcoma and acute lymphoblastic leukemia (ALL) (Gutierrez-Caminoet al., 2014; Bilbao-Aldaiturriaga et al., 2015). CNOT1 depletioninduces stabilization of mRNAs and activation of ER stress-mediatedapoptosis (Ito et al., 2011).

Single nucleotide polymorphism in the CNOT4 gene was correlated with therisk of osteosarcoma (Bilbao-Aldaiturriaga et al., 2015).

Changes in COPA gene expression and RNA editing were shown to beassociated with hepatocellular carcinoma and an experimental studyrevealed anti-apoptotic effects of COPA in mesothelioma cells (Qi etal., 2014; Sudo et al., 2010; Wong et al., 2003).

shRNA library screening identified COPB1 as determinants of sensitivityto 2-deoxyglucose, a glycolytic inhibitor in cancer cells. Moreover,silencing of COPB1 expression sensitized cells to 2-deoxyglucosetoxicity (Kobayashi et al., 2015a).

COPB2 is expressed in various types of cancer such as breast, colon,prostate, pancreas carcinomas, glioblastoma and lung adenocarcinoma(Erdogan et al., 2009). Others have implicated COPB2 to be involved inanti-apoptotic function in mesothelioma (Sudo et al., 2010).

COPG1 correlates with the age of the patients as well as a higher gradeof malignancy and the grade of gliosarcomas (Coppola et al., 2014).COPG1 was found abundantly expressed in lung cancer and lungcancer-related endothelial cells (Park et al., 2008).

Function-based genomic screening identified COPZ1 as an essential genefor different tumor cells. Knock-down of COPZ1 was shown to cause Golgiapparatus collapse, block autophagy, and induce apoptosis in bothproliferating and non-dividing tumor cells. Thus, COPZ1 could be a noveltherapeutic target, which offers an opportunity forproliferation-independent selective killing of tumor cells (Shtutman etal., 2011).

Over-expression of CORO2A has been found in breast cancer and coloncarcinoma (Bubnov et al., 2012; Rastetter et al., 2015). Researchershave revealed that both MAPK14 and PRMT5 signaling pathways play acrucial role in tumor progression (Rastetter et al., 2015).Down-regulation of CORO2A in colorectal cancer cells was correlated withreduced early apoptosis (Kim et al., 2013a).

Single nucleotide polymorphisms as well as mutations in the CSDA genewere associated with hepatocellular carcinoma. Another group foundhigher mRNA expression levels of CSDA in hepatocellular carcinomacompared to corresponding non-tumor tissues. In addition, elevatedlevels of CSDA were observed in gastric cancer tissues and cell linescompared to adjacent normal tissues (Hayashi et al., 2002; Wang et al.,2009a; Yasen et al., 2012). Recent work has shown a correlation betweenelevated levels of CSDA in hepatocarcinomas and poorer prognosis (Yasenet al., 2005). In chronic myeloid leukemia, both Akt and MEK/p90ribosomal S6 kinase can phosphorylate the serine 134 residue of CSDA(Sears et al., 2010).

CSE1L was shown to be highly expressed in hepatocellular carcinoma,bladder urothelial carcinoma, serous ovarian cancer, breast cancer andmetastatic cancer (Behrens et al., 2001; Tung et al., 2009; Stawerski etal., 2010; Tai et al., 2012; Zang et al., 2012). Researchers havedemonstrated that CSE1L regulates translocation and secretion of MMP-2from colorectal cancer cells (Liao et al., 2008; Tsao et al., 2009).Furthermore, inhibition of MEK1 mediated phosphorylation resulted inenhanced paclitaxel (Taxol) induced apoptosis in breast, ovarian, andlung tumor cell lines. Since CSE1L is also activated by MEK1 alteringthe activity/phosphorylation status of CSE1L via MEK1 inhibition maypresent a potential strategy in experimental cancer therapy (Behrens etal., 2003).

CT45 genes were shown to be potential prognostic biomarkers andtherapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).The CT45A1 protein which is usually only expressed in testicular germcells was shown to be also expressed in lung cancer, breast cancer andovarian cancer (Chen et al., 2009d). CT45A1 was also shown to beassociated with poor prognosis and poor outcomes in multiple myeloma(Andrade et al., 2009). CT45A1 was described as gene up-regulatingepithelial-mesenchymal transition (EMT) and metastatic genes, promotingEMT and tumor dissemination. Furthermore, CT45A1 was described as beingimplicated in the initiation or maintenance of cancer stem-like cells,promoting tumorigenesis and malignant progression (Yang et al., 2015a).CT45A1 over-expression in a breast cancer model was shown to result inthe up-regulation of various oncogenic and metastatic genes,constitutively activated ERK and CREB signaling pathways and increasedtumorigenesis, invasion and metastasis. Silencing of CT45A1 was shown toreduce cancer cell migration and invasion. Thus, CT45A1 may function asa novel proto-oncogene and may be a target for anticancer drug discoveryand therapy (Shang et al., 2014).

CT45A2 was shown to be a novel spliced MLL fusion partner in a pediatricpatient with de novo bi-phenotypic acute leukemia and thus might berelevant for leukemogenesis (Cerveira et al., 2010). The cancer/testisantigen family 45 was shown to be frequently expressed in both cancercell lines and lung cancer specimens (Chen et al., 2005). CT45 geneswere shown to be potential prognostic biomarkers and therapeutic targetsin epithelial ovarian cancer (Zhang et al., 2015l).

The cancer/testis antigen family 45 was shown to be frequently expressedin both cancer cell lines and lung cancer specimens (Chen et al., 2005).CT45 genes were shown to be potential prognostic biomarkers andtherapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

The cancer/testis antigen family 45 was shown to be frequently expressedin both cancer cell lines and lung cancer specimens (Chen et al., 2005).CT45 genes were shown to be potential prognostic biomarkers andtherapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

The cancer/testis antigen family 45 was shown to be frequently expressedin both cancer cell lines and lung cancer specimens (Chen et al., 2005).CT45 genes were shown to be potential prognostic biomarkers andtherapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

The cancer/testis antigen family 45 was shown to be frequently expressedin both cancer cell lines and lung cancer specimens (Chen et al., 2005).CT45 genes were shown to be potential prognostic biomarkers andtherapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

Elevated levels of CTSA were found in squamous cell carcinoma comparedto normal mucosa. Others have detected higher levels of CTSA activity inlysates of metastatic lesions of malignant melanoma than in primaryfocus lysates. Another report has demonstrated that the CTSA activitywas twice as high in the vitreous body of patients suffering fromabsolute glaucoma compared to patients with intraocular tumors(Obuchowska et al., 1999; Kozlowski et al., 2000; Marques Filho et al.,2006).

CYFIP1 was shown to be down-regulated during invasion of epithelialtumors (Silva et al., 2009). CYFIP1 down-regulation is associated withpoor prognosis in epithelial tumors (Silva et al., 2009).

CYFIP2 expression is increased in newly formed lymph nodes in breastcancer (Gantsev et al., 2013). CYFIP2 expression is reduced in humangastric tumor samples, compared with control tissues (Cheng et al.,2013b). CYFIP2 is one of several apoptosis-related genes methylated inchronic lymphocytic leukemia (Halldorsdottir et al., 2012).

The expression of CYP2F1 was found in primary ovarian cancer andnon-cancerous nasopharynx tissues. However, it was absent in breasttumors as well as in control tissues (Downie et al., 2005; Iscan et al.,2001; Jiang et al., 2004). In colorectal cancer, the expression ofCYP2F1 in the lymph node metastasis strongly correlated with itspresence in corresponding primary tumors (Kumarakulasingham et al.,2005).

CYP4X1 was shown to be present as an off-frame fusion transcript withCYP4Z2P in breast cancer (Kim et al., 2015a). CYP4X1 was shown to beassociated with tumor grade in breast cancer and may be a potentialbiomarker to aid decisions regarding optimal adjuvant hormonal therapy(Murray et al., 2010). CYP4X1 was shown to be a potential primary targetof estrogen receptor beta (ERbeta) in the ERbeta over-expressing HEK293cell line (Zhao et al., 2009).

A single polymorphism in the CYP7B1 gene has been associated with therisk of prostate cancer. In addition, elevated levels of CYP7B1 havebeen found in high-grade prostatic intraepithelial neoplasia,adenocarcinomas and breast carcinoma (Jakobsson et al., 2004; Olsson etal., 2007; Pu et al., 2015).

DCBLD2 is up-regulated in glioblastomas and head and neck cancers (HNCs)and is required for EGFR-stimulated tumorigenesis (Feng et al., 2014a).Furthermore, DCBLD2 is up-regulated in highly metastatic lung cancersublines and tissue samples (Koshikawa et al., 2002). In contrast, theexpression of DCBLD2 is silenced by hypermethylation of its promoter ingastric cancer (Kim et al., 2008b).

DCHS2 is associated with gastric cancers and colorectal cancers withhigh microsatellite instability (An et al., 2015).

DDX11, belonging to the DEAH family of DNA helicases, is highlyexpressed in advanced melanoma and is essential for the survival ofmelanoma cells (Bhattacharya et al., 2012).

DDX20 was shown to be down-regulated in hepatocellular carcinoma (Takataet al., 2013a). DDX20 is associated with increased risk of colorectalcancer and bladder cancer as well as reduced overall survival in breastcancer and increased metastatic potential (Yang et al., 2008a; Zhao etal., 2015b; Shin et al., 2014). DDX20 may be a prognostic biomarker forbreast cancer (Shin et al., 2014).

DDX41 is associated with acute myeloid leukemia (Antony-Debre andSteidl, 2015).

DDX47 may be a potential marker to discriminate different disease phasesof chronic myeloid leukemia (Oehler et al., 2009).

DDX6 was found to be over-expressed in colorectal adenocarcinomas,gastric cancer, hepatocellular carcinoma, nodal marginal zone lymphoma,neuroblastoma, rhabdomyosarcoma and lung cancer cell lines (Akao et al.,1995; Nakagawa et al., 1999; Miyaji et al., 2003; Lin et al., 2008a;Stary et al., 2013; lio et al., 2013). In nodal marginal zone lymphoma,DDX6 seems to interfere with the expression of BCL6 and BCL2 in an NF-Î^(o) B independent manner (Stary et al., 2013). Recent studies haveshown that DDX6 post-transcriptionally down-regulated miR-143/145expression by prompting the degradation of its host gene product,NCR143/145 RNA (Iio et al., 2013).

DEPDC1B was shown to be up-regulated in oral cancer and non-small celllung cancer (Yang et al., 2014e; Su et al., 2014). DEPDC1B expression isassociated with patient survival, migration and metastasis of non-smallcell lung cancer and radiation sensitivity of lymphoblastoid tumor celllines (Niu et al., 2010; Yang et al., 2014e).

High levels of the DFFB gene were detected in cisplatin resistance inbladder cancer, whereas the levels of DFFB were decreased inoligodendrogliomas with 1p-allelic loss. Another group found no mutationin the DFFB gene in neuroblastomas (Judson et al., 2000; McDonald etal., 2005; Kim et al., 2016). Over-expression of DFFB resulted in adecrease in the viability of breast cancer cells incubated withacetazolamide and sulfabenzamide. In addition, there was enhancedapoptosis in these groups, especially with acetazolamide. Similarly,DFFB fused with GM-CSF was found to facilitate targeted killing of acutemyeloid leukemia cells by inducing apoptosis (Mathew et al., 2013;Bagheri et al., 2014).

DFNA5 expression was found to be lower in hepatocellular carcinomacells, estrogen receptor (ER)-positive breast carcinoma and gastriccancer cell lines (Thompson and Weigel, 1998; Akino et al., 2007; Wanget al., 2013c). Moreover, etoposide resistance in melanoma cells waslinked to reduced DFNA5 expression (Lage et al., 2001). DFNA5 knock-downresulted in an increase in cell invasion, colony numbers, colony sizeand cell growth in colorectal carcinoma cell lines (Kim et al., 2008c).

DHX40 is associated with epithelial ovarian cancer (Zheng et al., 2004).

PrognoScan database revealed that DHX8 is expressed in bladder cancer,blood cancer, brain cancer, breast cancer, colorectal cancer, eyecancer, head and neck cancer, lung cancer, ovarian cancer, skin cancerand soft tissue cancer tissues (Wang et al., 2014f).

Researchers have observed that DHX8 was present both in the normaladrenal cortex as well as in the malignant adrenocortical cancer (Szaboet al., 2009).

DEF was shown to mediate the non-proteasomal degradation of thetumor-suppressor p53 (Tao et al., 2013).

Studies have revealed that DLG5 is down-regulated in prostate cancer aswell as bladder cancer. On the other hand, over-expression of DLG5 wasobserved in pancreatic ductal adenocarcinoma. Moreover, singlenucleotide polymorphisms in the DLG5 gene were not correlated with riskof colorectal cancer (Taniuchi et al., 2005; Suchy et al., 2008;Tomiyama et al., 2015; Zhou et al., 2015b). Knockdown of endogenous DLG5resulted in an increase in prostate cancer cell migration and invasion,while it suppressed the growth of pancreatic ductal adenocarcinoma(Taniuchi et al., 2005; Tomiyama et al., 2015).

DMXL2 was shown to be up-regulated in ER-alpha positive breast cancer(Faronato et al., 2015). DMXL2 is a functional biomarker for ER-alphapositive breast cancer (Faronato et al., 2015).

DNAH3 is associated with colon cancer (Tanaka et al., 2008a).

Studies have detected DNASE1L1 in patients suffering from oral squamouscell carcinoma. Furthermore, DNASE1L1 expression was linked with poordisease-free survival rate in these patients (Grimm et al., 2013).

DOCK8 was shown to be down-regulated in squamous cell carcinoma of thelung (Kang et al., 2010). DOCK8 was shown to be associated withneuroblastomas, pediatric pilocytic astrocytomas, hepatocellularcarcinomas, gliomas and lung cancer (Schramm et al., 2015; Saelee etal., 2009; Takahashi et al., 2006; Zhao et al., 2014a; Idbaih et al.,2008). DOCK8 was shown to be associated with radiosensitivity in theesophageal cancer cell line TE-11 (Ogawa et al., 2008).

A report has revealed over-expression of DPP3 in glioblastoma cells aswell as in squamous cell lung carcinoma. Similarly, higher DPP3 activitywas observed in endometrial and ovarian malignant tumors compared to theactivity in normal tissues (Simaga et al., 1998; Simaga et al., 2003;Hast et al., 2013; Singh et al., 2014).

DPPA4 was shown to be up-regulated in colon cancer (Zhang et al.,2015j). DPPA4 is associated with bladder cancer, prostate cancer,embryonal carcinomas, pluripotent germ cell tumors and sarcoma (Tung etal., 2013; Amini et al., 2014). DPPA4 is associated with stage, invasiondepth, distant metastasis and differentiation of colon cancer (Zhang etal., 2015j). DPPA4 is an independent prognostic indicator ofdisease-free survival and overall survival of colon cancer (Zhang etal., 2015j).

DTX3L was shown to be up-regulated in melanomas, squamous cellcarcinomas of the cervix and diffuse large B-cell lymphomas with aprominent inflammatory infiltrate (Thang et al., 2015; Wilting et al.,2008; Juszczynski et al., 2006). DTX3L was shown to mediate regulationof invasion and metastasis in melanoma through FAK/PI3K/AKT signaling.Thus, DTX3L may serve as a potential therapeutic target as well as apotential biomarker for melanomas (Thang et al., 2015). DTX3L wasdescribed as a chemotherapy resistance factor which is up-regulated inEZH2 gain-of-function mutant diffuse large B-cell lymphomas (Johnson etal., 2015). DTX3L was shown to be a novel oncogenic factor in metastaticprostate cancer cells which mediates proliferation, chemo-resistance andsurvival of metastatic prostate cancer in interaction with oncogenicproteins ARTD8 and ARTD9 (Bachmann et al., 2014). DTX3L was shown to beassociated with transcription factors STAT1 and STAT3 as well as thetumor suppressor IRF1 in metastatic prostate cancer cells (Bachmann etal., 2014). DTX3L was described as a bona fide member of a DNA damageresponse pathway, which is directly associated with PARP1 activation andrecruitment of the tumor suppressor BRCA1 (Yan et al., 2013b).

A whole exome sequencing study uncovered somatic mutations within theDYNC1H1 gene in patients with intra-ductal papillary mucinous neoplasmof the pancreas (Furukawa et al., 2011).

DYNC2H1 was shown to be up-regulated in glioblastoma multiforme (Yokotaet al., 2006).

EGFLAM promoter CGI methylation ratio was decreased in epithelialovarian cancer compared to benign ovarian diseases (Gu et al., 2009).The promoter CGI of EGFLAM may be a novel candidate for ovariancancer-specific hypo-methylated tumor markers (Gu et al., 2009).

EIF2S2 has been shown to be amplified in patients suffering from highlyproliferative luminal breast tumors (Gatza et al., 2014).

EIF2S3 is one of 5 molecular markers that were differentially expressedbetween peripheral blood samples of colorectal cancer patients andhealthy controls (Chang et al., 2014c). EIF2S3 interacts with N-mycdown-stream regulated gene 1 (NDRG1), which plays a role in celldifferentiation and inhibition of prostate cancer metastasis (Tu et al.,2007).

EIF3C is highly expressed in colon cancer (Song et al., 2013c). EIF3CmRNA is over-expressed in testicular seminomas (Rothe et al., 2000).

Down-regulation of EIF3F expression was reported in pancreatic cancerand in melanoma. Furthermore, loss of EIF3F and a statisticallysignificant reduced gene copy number was demonstrated in both melanomaand pancreatic tumors as compared to normal tissues (Shi et al., 2006;Doldan et al., 2008a; Doldan et al., 2008b). Recent work showed thatdecreased expression of EIF3F could be used as a prognostic marker forpoor outcome in patients affected by gastric cancer (Cheng et al.,2015a). High levels of EIF3F inhibited cell proliferation and inducedapoptosis in melanoma and pancreatic cancer cells (Shi et al., 2006;Doldan et al., 2008a).

EIF4G3 is up-regulated in diffuse large B-cell lymphoma. Moreover,down-regulation of EIF4G3 by siRNA resulted in a reduction oftranslation, cell proliferation and the ability to form colonies as wellas induction of cellular senescence (Mazan-Mamczarz et al., 2014).

EMC10 up-regulation was shown to be associated with high-grade gliomasand modulation of signaling pathways involved in tumorigenesis(Junes-Gill et al., 2011; Junes-Gill et al., 2014). EMC10 was shown toinhibit glioma-induced cell cycle progression, cell migration, invasionand angiogenesis and thus may be a potential therapeutic for malignantglioblastoma (Junes-Gill et al., 2014).

Down-regulation of EMG1 was noted in hepatocellular carcinoma cell linesafter treatment with platycodin D (Lu et al., 2015).

EPG5 is associated with breast cancer (Halama et al., 2007).

EPPK1 was shown to be associated with intrahepatic cholangiocarcinomaand cervical squamous cell carcinoma (Zou et al., 2014b; Guo et al.,2015).

ERLIN2 is associated with breast cancer and hepatocellular carcinoma(Wang et al., 2012a).

ERMP1 was shown to be associated with breast cancer (Wu et al., 2012c).

Mutations and single nucleotide polymorphisms of ESR1 are associatedwith risk for different cancer types including liver, prostate,gallbladder and breast cancer. The up-regulation of ESR1 expression isconnected with cell proliferation and tumor growth but the overallsurvival of patients with ESR1 positive tumors is better due to thesuccessfully therapy with selective estrogen receptor modulators (Sun etal., 2015c; Hayashi et al., 2003; Bogush et al., 2009; Miyoshi et al.,2010; Xu et al., 2011; Yakimchuk et al., 2013; Fuqua et al., 2014). ESR1signaling interferes with different pathways responsible for celltransformation, growth and survival like the EGFR/IGFR, PI3K/Akt/mTOR,p53, HER2, NFkappaB and TGF-beta pathways (Frasor et al., 2015; Band andLaiho, 2011; Berger et al., 2013; Skandalis et al., 2014; Mehta andTripathy, 2014; Ciruelos Gil, 2014).

ESRRG signaling has been correlated with reduced distant metastasis-freesurvival in ER+ breast cancer treated with tamoxifen (Madhavan et al.,2015). Recent work demonstrated that ESRRG mediated the effects ofestrogen on the proliferation of endometrial cancer cells via theactivation of AKT and ERK1/2 signaling pathways (Sun et al., 2014c).High levels of ESRRG induced proliferation in ER+ breast cancer cells inthe presence or absence of estrogen. In contrast, silencing of ESRRGinhibited hepatocellular carcinoma cell lines growth and induced cellapoptosis (Ijichi et al., 2011; Yuan et al., 2015).

EXOC8 was shown to interact with the cancer-associated Ras-like smallGTPase RalA in the brain (Das et al., 2014). EXOC8 interaction with RalAwas described as necessary for migration and invasion of prostate cancertumor cells (Hazelett and Yeaman, 2012). EXOC8 was shown to be involvedin the tumor-promoting function of dermal fibroblasts, which is executedby RalA. The RalA signaling cascade in dermal fibroblasts involves EXOC8and was described as a potential anti-cancer target upon progression ofsquamous cell carcinoma of the skin (Sowalsky et al., 2011). EXOC8 wasdescribed as a protein fostering oncogenic ras-mediated tumorigenesis(Issaq et al., 2010).

EXOSC4 promotor activity is increased in hepatocellular carcinoma, dueto DNA hypomethylation. EXOSC4 effectively and specifically inhibitscancer cell growth and cell invasive capacities (Stefanska et al., 2014;Drazkowska et al., 2013).

EXOSC7 is associated with cervical cancer (Choi et al., 2007).

In gastric tumor tissues, the expression of EYA1 is significantlydecreased compared with adjacent normal tissues. Moreover, EYA1 wassignificantly over-expressed in Wilms tumors (Li et al., 2002; Nikpouret al., 2014). It is reported that genetic silencing of EYA1significantly sensitizes breast cancer cells to pharmacologicalinhibition of PI3K/Akt signaling. These findings imply that they mayfunction together to regulate cancer cell behavior (Sun et al., 2015g).

EYA2 over-expression has been observed in several tumor types, such asepithelial ovarian tumor, prostate, breast cancer, urinary tractcancers, glioblastoma, lung adenocarcinoma, cervical cancer, colon andhematopoietic cancers (Bierkens et al., 2013; Zhang et al., 2005a; Guoet al., 2009; Patrick et al., 2013; Kohrt et al., 2014). Studies haverevealed that EYA2 influences transcription of TGF beta pathway membersas well as phosphorylation of TGFBR2, implying a dual role of EYA2 inthe pancreas (Vincent et al., 2014).

EYA3 is highly expressed in Ewing sarcoma tumor samples and cell linescompared with mesenchymal stem cells. On the other hand, deletion of theEYA3 gene has been linked to certain pancreatic ductal adenocarcinomas(Gutierrez et al., 2011; Robin et al., 2012). Recent work has shown thatover-expression of EYA3 results in increased proliferation, migration,invasion and transformation of breast cancer cells (Pandey et al.,2010).

It has been reported that EYA4 is frequently and concomitantly deleted,hyper-methylated and under-expressed in non-small-cell lung cancersubtypes as well as in the earliest stages of lung cancer and inadenocarcinoma in situ, colorectal cancer and hepatocellular carcinoma(Selamat et al., 2011; Wilson et al., 2014; Hou et al., 2014; Kim etal., 2015c). In colorectal cancer, EYA4 is a tumor suppressor gene thatacts by inducing up-regulation of DKK1 and inhibiting the Wnt signalingpathway (Kim et al., 2015c).

Expression analyses have shown FABP7 transcripts in tumors or urine ofpatients with renal cell carcinoma, as well as in tissues ofglioblastoma and melanoma (Liang et al., 2005; Seliger et al., 2005;Goto et al., 2010; Takaoka et al., 2011). In addition, FABP7over-expression in glioblastoma and melanoma correlates with shortersurvival (Liang et al., 2006; Slipicevic et al., 2008). In glioma celllines, NFI de-phosphorylation is correlated with FABP7 expression(Bisgrove et al., 2000).

FADS2 is up-regulated in hepatocellular carcinoma (Muir et al., 2013).FADS2 activity is increased in breast cancer tissue (Pender-Cudlip etal., 2013). FADS2 expression is associated with aggressiveness of breastcancer (Lane et al., 2003). FADS2 inhibition impedes intestinaltumorigenesis (Hansen-Petrik et al., 2002).

FAM135B is associated with esophageal squamous cell carcinoma (Song etal., 2014b).

FAM86A was shown to interact with the tumor-associated eukaryoticelongation factor 2 (Davydova et al., 2014).

Down-regulation or dysfunction of FANCD2 due to genetic mutations hasbeen reported in different cancer types including breast cancer, acutelymphatic leukemia and testicular seminomas and is associated withcancer development. Otherwise also re-expression and up-regulation ofFANCD2 was shown to be associated with tumor progression and metastasisin gliomas and colorectal cancer (Patil et al., 2014; Shen et al.,2015a; Shen et al., 2015b; Ozawa et al., 2010; Rudland et al., 2010;Zhang et al., 2010a; Smetsers et al., 2012). PI3K/mTOR/Akt pathwaypromotes FANCD2 inducing the ATM/Chk2 checkpoint as DNA damage responseand mono-ubiquitinilated FANCD2 activates the transcription of the tumorsuppressor TAp63 (Shen et al., 2013; Park et al., 2013).

The expression level of FANCG mRNA in newly diagnosed acute myeloidleukemia patients is significantly lower than that in control and acutemyeloid leukemia complete remission groups. Moreover, germline mutationsof FANCG might contribute to the progression of pancreatic cancer. Incontrast, mutations in FANCG could not be detected in bladder carcinomacell lines (Couch et al., 2005; Neveling et al., 2007; Duan et al.,2013). Endogenous disruption of FANCG in a human adenocarcinoma cellline resulted in increased clastogenic damage, G2/M arrest and decreasedproliferation (Gallmeier et al., 2006).

Mutations in the FAT2 gene have been found in esophageal squamous cellcarcinoma as well as head and neck squamous cell carcinoma. In addition,FAT2 mRNA was expressed in gastric cancer, pancreatic cancer and ovariancancer (Katoh and Katoh, 2006; Lin et al., 2014; Gao et al., 2014).

FAT3 was shown to be down-regulated in taxol resistant ovarian carcinomacell lines upon silencing of androgen receptor, resulting in increasedsensitization to taxol in these cell lines. Thus, FAT3 may be acandidate gene associated with taxol resistance (Sun et al., 2015e).FAT3 was shown to be mutated in esophageal squamous cell carcinoma,resulting in dysregulation of the Hippo signaling pathway (Gao et al.,2014). FAT3 was shown to be mutated recurrently in early T-cellprecursor acute lymphoblastic leukemia (Neumann et al., 2013). FAT3 wasdescribed as a gene with signatures specific for meningothelialmeningiomas, therefore being associated with tumorigenesis in thissubtype of benign meningiomas (Fevre-Montange et al., 2009). FAT3 wasdescribed as a tumor suppressor which is repressed upon lung cancerdevelopment from dysplastic cells (Rohrbeck and Borlak, 2009).

FBXO4 was shown to be down-regulated in hepatocellular carcinoma (Chu etal., 2014). FBXO4 is associated with esophageal squamous cell carcinoma,melanoma, lymphomas and histiocytic sarcomas (Vaites et al., 2011; Leeet al., 2013b; Lian et al., 2015).

FBXO5 was shown to be up-regulated in breast cancer and hepatocellularcarcinoma (Zhao et al., 2013c; Liu et al., 2014h). FBXO5 was shown to bedown-regulated in primary gastric cancer (Zhang et al., 2014e). FBXO5 isassociated with invasion and metastatic potential in breast cancer,tumor size, infiltration, clinical grade and prognosis in gastriccancer, histologic grade in breast cancer, histologic grade and pooroverall survival in ovarian clear cell carcinoma, stage and prognosis inhepatocellular carcinoma and poor prognosis in esophageal squamous cellcarcinoma (Kogo et al., 2011; Zhao et al., 2013c; Min et al., 2013; Liuet al., 2013d; Zhang et al., 2014e; Liu et al., 2014h). FBXO5 isassociated with breast cancer, ovarian cancer, hepatocellular cancer,prostate cancer and mantle cell lymphoma (Johansson et al., 2014;Schraders et al., 2008). FBXO5 is a prognostic predictor of breastcancer and esophageal squamous cell carcinoma (Kogo et al., 2011; Liu etal., 2014h).

FBXW8 was shown to be up-regulated in choriocarcinoma (Shi et al.,2014a). FBXW8 is associated with pancreatic cancer and choriocarcinoma(Wang et al., 2014b; Lin et al., 2011).

FGFR1OP is associated with chronic myelomonocytic leukemia, acutemyeloid leukemia and myeloproliferative neoplasms (Hu et al., 2011;Bossi et al., 2014). FGFR1OP was shown to be up-regulated in lung cancer(Mano et al., 2007). FGFR1OP expression is associated with shortertumor-specific survival times (Mano et al., 2007). FGFR1OP is aprognostic biomarker for lung cancer (Mano et al., 2007).

Over-expression of FIG. 4 was found in the triple negative breast cancercompared to non-tumorigenic cells (Ikonomov et al., 2013).

FLAD1 was shown to be associated with non-small cell lung cancer (Mitraet al., 2011).

Depending on its subcellular localization, filamin A plays a dual rolein cancer: In the cytoplasm, filamin A functions in various growthsignaling pathways, in addition to being involved in cell migration andadhesion pathways. Thus, its over-expression has a tumor-promotingeffect. In contrast to full-length filamin A, the C-terminal fragment,which is released upon proteolysis of the protein, localizes to thenucleus, where it interacts with transcription factors and therebysuppresses tumor growth and metastasis (Savoy and Ghosh, 2013).

Over-expression of FOXM1 has been found in a variety of aggressive humancarcinomas including lung cancer, glioblastomas, prostate cancer, basalcell carcinomas, hepatocellular carcinoma, primary breast cancer andpancreatic cancer (Teh et al., 2002; Kalinichenko et al., 2004; Kalin etal., 2006; Kim et al., 2006; Liu et al., 2006; Wang et al., 2007b).Recent study suggest that the FOXM1 gene is up-regulated in pancreaticcancer due to transcriptional regulation by the Sonic Hedgehog pathway(Katoh and Katoh, 2004).

Several lines of evidence have implicated GAB2 in cancer, for instanceelevated levels of GAB2 were found in breast cancer, ovarian cancer aswell as some metastatic melanomas. Others have revealed that GAB2 isrequired for BCR/ABL-mediated transformation in chronic myeloid leukemia(Sattler et al., 2002; Daly et al., 2002; Horst et al., 2009; Wang etal., 2012c). In ovarian cancer, over-expression of GAB2 resulted in theactivation of the phosphatidylinositol 3-kinase pathway (Dunn et al.,2014).

GADD45GIP1 was shown to interact with leukemia-associated Lck (Vahedi etal., 2015). GADD45GIP1 was shown to be down-regulated in acute myeloidleukemia (Ran et al., 2014). GADD45GIP1 was shown to have a tumorsuppressor effect in the cervical and ovarian cancer cell lines HeLa andSKOV3 (Nakayama et al., 2007). GADD45GIP1 was shown to interact with thetumor suppressor STAT3 in prostate cancer and with CDK2 as acyclin-dependent kinase inhibitor (Ran et al., 2014; Tan et al., 2014).GADD45GIP1 was shown to be negatively regulated by NAC1, which isconsidered to have adverse effects on prognosis in ovarian and cervicalcarcinomas (Nishi et al., 2012). GADD45GIP1 was shown to be associatedwith paclitaxel resistance in ovarian cancer (Jinawath et al., 2009).GADD45GIP1 may play an important role in the regulation of androgenreceptor (AR)-positive growth of prostate cancer through its function asan AR corepressor (Suh et al., 2008). GADD45GIP1 was shown to beup-regulated in lymph node (+) breast carcinomas (Abba et al., 2007).

The expression of GART is significantly up-regulated in human glioma andhepatocellular carcinoma. Single nucleotide polymorphisms in GART aresignificantly associated with hepatocellular carcinoma risk in theChinese population (Liu et al., 2014g; Cong et al., 2014; Zhang et al.,2015e). In hepatocellular carcinoma, over-expression of GART correlatedpositively with the histologic grade, tumor size, number of tumorousnodes and intrahepatic metastases (Cong et al., 2014). GART is able toact as a regulator of tumor progression and survival in renal cellcarcinoma by targeting tumor associated macrophages (Ohba et al., 2005).

GAS2L3 was shown to be down-regulated in the gastric cancer cell lineHSC45-M2 upon incubation in lethal doses of (213)Bi-d9Mab. Thus, GAS2L3might be a new target for selective elimination of tumor cells (Seidl etal., 2010).

GBGT1 is associated with ovarian cancer and oral squamous cell carcinoma(Viswanathan et al., 2003; Jacob et al., 2014).

GGT6 was shown to be amplified in a patient with choroid plexuspapilloma (de Leon et al., 2015).

Researchers have observed higher mRNA transcript levels of GNB1 inbreast cancer specimens compared to normal glandular tissue. Inendometrial cancer, the expression of GNB1 was significantly changed incomparison to the control group (Orchel et al., 2012; Wazir et al.,2013). Furthermore, the mRNA expression of GNB1 increased with TNMstage, tumor grade and was linked with adverse patient outcomes (Waziret al., 2013).

GON4L is associated with hepatocellular carcinoma and salivary glandcancer (Simons et al., 2013; Kim et al., 2009b).

The variable number of tandem repeats polymorphism of the GP1BA gene hasbeen associated with the risk of oral and breast cancer. On thecontrary, others did not detect any association between the variablenumber of tandem repeats polymorphism of the GP1BA gene and breastcancer aggressiveness (Oleksowicz et al., 1998; Ayala et al., 2003;Vairaktaris et al., 2007). In breast cancer, GP1BA expression correlatedsignificantly with tumor stage, tumor size and estrogen receptornegativity (Oleksowicz et al., 1998).

GPD2 abundance and activity is significantly up-regulated in prostatecancer cells and is associated with the high reactive oxygen species(ROS) production in cancer cells (Chowdhury et al., 2005; Chowdhury etal., 2007).

In breast cancer cell lines, knockdown of GPR64 resulted in a strongreduction in cell adhesion as well as in cell migration (Peeters et al.,2015).

GPX5 rs451774 was found to be associated with overall survival inpatients suffering from non-small cell lung cancer receiving platinumplus gemcitabine treatment (Li et al., 2011c).

GRAMD1A was shown to be expressed in cancer cell lines (Song et al.,2014a).

GRHL2 was shown to be up-regulated in colorectal cancer and oralsquamous cell carcinoma (Quan et al., 2015b; Kang et al., 2009). GRHL2was shown to be down-regulated in cervical cancer and diverse breastcancer subclasses (Cieply et al., 2012; Torres-Reyes et al., 2014).GRHL2 was shown to be associated with poor prognosis in colorectalcancer, lower disease-free survival in clear cell renal cell carcinomaand poor relapse free survival in breast cancer (Butz et al., 2014; Quanet al., 2015b; Xiang et al., 2012). GRHL2 was shown to be associatedwith metastasis in breast cancer and hepatocellular carcinoma (Tanaka etal., 2008b; Werner et al., 2013). GRHL2 may be a prognostic biomarkerfor colorectal cancer, clear cell renal cell carcinoma andhepatocellular carcinoma (Butz et al., 2014; Quan et al., 2015b; Tanakaet al., 2008b).

GRIK3 is associated with lung adenocarcinoma (methylation, functionalmodifications), pediatric central nervous system tumors, lymphocyticleukemia, and neuroblastoma (Pradhan et al., 2013). GRIK3 isdifferentially expressed in several pediatric tumors of the centralnervous system (Brocke et al., 2010).

Over-expression or somatic mutations of GRIN2D was found in pediatriccentral nervous system tumors, human breast cancers as well as prostatecancer cell lines. In addition, knockdown of GRIN2D did not influencecancer phenotype in TE671 and RPM18226 cancer cell lines (Brocke et al.,2010; Pissimissis et al., 2009; Luksch et al., 2011; Jiao et al., 2012).

GSDMA was described as frequently silenced in gastric cancer cell linesand to be associated with apoptosis (Lin et al., 2015a). GSDMA was shownto be mutated in the 3′-UTR in different cancers, resulting in thecreation or disruption of putative microRNA target sites, thus,potentially resulting in dysregulation of gene expression (Ziebarth etal., 2012). Expression analysis of GSDMA in esophageal and gastriccancer suggests that GSDMA is a tumor suppressor (Saeki et al., 2009).

Breast cancer patients exhibited higher frequency of homozygous deletionof the GSTM1 gene compared with the control group. Genetic polymorphismof the GSTM1 gene has been also associated with bladder cancersusceptibility in the Iranian population, lung cancer risk in theChinese population, prostate, esophageal and cervical cancer in theIndian population (Mittal et al., 2004; Singh et al., 2008; Safarinejadet al., 2013; Sharma et al., 2013; Possuelo et al., 2013; Chen et al.,2014g).

Studies have shown frequent down-regulation and promoter DNAhyper-methylation of GSTM5 in Barrett's adenocarcinoma compared tonormal samples. On the other hand, GSTM5 transcript was not detected inacute lymphoblastic leukemia patients (Kearns et al., 2003; Peng et al.,2009). Researchers have observed that single-nucleotide polymorphisms inGSTM5 gene may affect overall survival in stages I to II or low-stagenon-small cell lung cancer (Pankratz et al., 2011).

GSTT2 promoter polymorphisms and their haplotypes are associated withcolorectal cancer risk in the Korean population. Others have reportedthat deletion in the GSTT2 gene may have a protective effect on theinitiation and development of esophageal squamous cell carcinoma in theMixed Ancestry South African population. In addition, low frequency ofDNA methylation of GSTT2 gene was found in Barrett's adenocarcinoma(Peng et al., 2009; Jang et al., 2007; Matejcic et al., 2011).

GSTT2B was shown to be associated with esophageal squamous cellcarcinoma since a GSTT2B deletion had a potential protective effect onthe risk of esophageal squamous cell carcinoma in the Mixed AncestrySouth African population (Matejcic et al., 2011).

Single nucleotide polymorphisms in the GTF2H4 gene were reported toincrease the risk to develop smoking-related lung cancer and papillomavirus-induced cervical cancer (Buch et al., 2012; Mydlikova et al.,2010; Wang et al., 2010).

Researchers have observed GTF21RD1-ALK fusion in thyroid cancer(Stransky et al., 2014).

Researchers have identified GTF3C2 as a novel ALK fusion in a cohort ofSpitz tumors (Yeh et al., 2015).

Several publications have reported down-regulation of H2AFY in varietyof human cancers including colorectal, lung, testicular, bladder,cervical, breast, colon, ovarian and endometrial (Novikov et al., 2011;Sporn and Jung, 2012). Additionally, knockdown of H2AFY in melanomacells resulted in significantly increased proliferation and migration invitro and growth and metastasis in vivo (Kapoor et al., 2010). Inbladder cancer, depletion of H2AFY expression was significantlyassociated with elevated levels of Lin28B expression (Park et al.,2016).

HAUS3 is associated with breast cancer (Shah et al., 2009).

High level of HDGF expression has been linked with poor prognosis inbreast cancer and pancreatic ductal carcinoma (Uyama et al., 2006; Chenet al., 2012b). Studies have revealed that HDGF plays an important rolein inducing cancer cell proliferation, angiogenesis, invasion andmigration in various malignancies such as oral squamous cell carcinoma,gastric, colonic, lung and esophageal cancers (Yamamoto et al., 2007;Mao et al., 2008; Liao et al., 2010; Meng et al., 2010; Lin et al.,2012; Tao et al., 2014a).

HEATR1 was shown to be up-regulated in glioblastoma (Wu et al., 2014c).

HELQ was described to interact with the RAD51 paralog complex BCDX2.Different components of this complex are associated with increased riskof ovarian cancer and breast cancer, respectively (Pelttari et al.,2015). HELQ was shown to be a candidate ovarian cancer gene due to itsassociation with RAD51 paralogs (Takata et al., 2013b). HELQ, as part ofthe polymerase pathway, was shown to be associated with oralcavity/pharynx cancers due to a missense mutation in the second exon(Babron et al., 2014). HELQ was shown to play a role in DNA repair andtumor suppression (Adelman et al., 2013). HELQ was shown to beassociated with esophageal squamous cell carcinoma using a genome-wideassociation study in a Han Chinese population (Li et al., 2013b).

HELZ2 was shown to be one biomarker in gene panel allowing earlierdiagnosis of epithelial ovarian cancer (Pils et al., 2013).

The HERC2/OCA2 region on chromosome 15q13.1 is one of several loci thatpredispose to cutaneous melanoma (Amos et al., 2011; Xiao et al., 2014).HERC2 regulates the stability of different DNA repair factors includingCHK1, p53 and BRCA1 (Bekker-Jensen et al., 2010; Cubillos-Rojas et al.,2014; Zhu et al., 2014a; Peng et al., 2015c).

HINT1 is transcriptionally silenced or down-regulated in various cancersincluding hepatocellular carcinoma, some human non-small cell lungcancer cell lines and gastric cancer. In contrast, HINT1 isover-expressed in prostate cancer (Zhang et al., 2009; Huang et al.,2011; Symes et al., 2013). It has been observed that in a hepatoma cellline, HINT1 inhibits activity of Wnt/beta-catenin signaling and genetranscription via TCF4 (Wang et al., 2009b).

It has been demonstrated that variants in the HLA-DMB gene could beassociated with the risk of HIV-related Kaposi's sarcoma. In addition,deregulation of HLA-DMB gene was noted in ERG-positive and ETV1-positiveprostate carcinomas (Paulo et al., 2012; Aissani et al., 2014).Furthermore, elevated levels of HLA-DMB expression in the tumorepithelium was correlated with improved survival in advanced serousovarian cancer (Callahan et al., 2008).

HLTF is a member of the SWI/SNF family of transcriptional regulatorswith helicase and E3 ubiquitin ligase activity and was found to beinactivated by hyper-methylation in colon, gastric, uterine, bladder andlung tumors (Castro et al., 2010; Debauve et al., 2008; Garcia-Baqueroet al., 2014).

HMMR expression is up-regulated in different cancer entities includingbreast, colon, gastric, pancreatic and prostate cancer and correlateswith cell motility, invasion and metastasis (Yamada et al., 1999; Wanget al., 1998; Abetamann et al., 1996; Gust et al., 2009; Ishigami etal., 2011; Sankaran et al., 2012). HMMR interacts with BRCA1 leading totumor progression by promoting genomic instability. Furthermore, HMMRassociates with Src, which elevates cell motility and HMMR-CD44partnering stimulates ERK signaling resulting in tumor promotion.Additionally, HMMR is a target of several tumor associated proteinsincluding E2F1, p53 and Ras (Blanco et al., 2015; Hall et al., 1995;Hall and Turley, 1995; Maxwell et al., 2008; Sohr and Engeland, 2008;Meier et al., 2014).

HSPA14 was shown to be up-regulated in hepatocellular carcinoma (Yang etal., 2015c). HSPA14 is associated with non-small cell lung cancer (Wu etal., 2011a).

HSPA8 was shown to be over-expressed in esophageal squamous cellcarcinoma and high expression levels of HSPA8 in esophageal cancer cellsin vitro counter-acted oxidative stress-induced apoptosis of thesecells. Furthermore, HSPA8 is over-expressed in multiple myeloma andcolonic carcinoma and BCR-ABL1-induced expression of HSPA8 promotes cellsurvival in chronic myeloid leukemia (Chatterjee et al., 2013; Dadkhahet al., 2013; Jose-Eneriz et al., 2008; Kubota et al., 2010; Wang etal., 2013b).

Over-expression of HUWE1 has been found in various types of tumors suchas lung carcinoma, breast carcinoma, prostate carcinoma, glioblastomaand colon carcinoma. Another report has revealed that HUWE1 isimplicated in the pathogenesis of hepatocellular carcinoma (Yoon et al.,2005; Adhikary et al., 2005; Liu et al., 2012). In addition, depletionof HUWE1 prevented the proliferation of a subset of human tumor cellswhile elevated levels of HUWE1 correlated with detectable p53 (Adhikaryet al., 2005; Confalonieri et al., 2009).

IDO1 was found to be expressed in a variety of tumors, such ascolorectal cancer, melanoma, serous ovarian cancer and papillary thyroidmicro-carcinoma (Brandacher et al., 2006; Takao et al., 2007; Brody etal., 2009; Ryu et al., 2014). Over-expression of IDO1 in endometrialcancer tissues as well as in childhood acute myeloid leukemia positivelycorrelated with disease progression and impaired patient survival (Inoet al., 2008; Folgiero et al., 2014).

IFI16 protein was relatively low or was not detectable in certain humanprostate and breast cancer cell lines (Xin et al., 2003; Alimirah etal., 2007). Researchers have noted that IFI16 is expressed in thehuman-papillomavirus-positive head and neck squamous cell carcinomas andcorrelates with a better prognosis (Azzimonti et al., 2004).Furthermore, treatment of breast cancer cell lines with 5-aza-dCresulted in up-regulation of IFI16 expression (Fujiuchi et al., 2004).

IFI30 expression was shown to be associated with diminished cellularactivation, including decrease of phosphorylated ERK1/2, decreasedcellular proliferation and cancer patient survival (Rausch and Hastings,2015). IFI30 was shown to be down-regulated in primary and metastaticbreast cancer (Xiang et al., 2014). Reduced IFI30 expression in breastcancer was shown to be associated with poorer disease-free survivalwhile absence of IFI30 was positively correlated with adversecharacteristics of breast cancers such as tumor size and lymph nodestatus (Xiang et al., 2014). Thus, IFI30 may act as a potential tumorsuppressor and novel independent prognostic factor in breast cancer(Xiang et al., 2014). Reduced IFI30 expression in diffuse large B-celllymphoma was shown to be associated with poor overall survival(Phipps-Yonas et al., 2013). A single nucleotide polymorphism in IFI30was shown to be a significant predictor for disease progression inadvanced prostate cancer patients treated with androgen-deprivationtherapy (Bao et al., 2011). IFI30 was shown to be one of several genesup-regulated in squamous cell carcinoma and basal cell carcinoma of theskin (Wenzel et al., 2008). IFI30 was shown to be associated withdisparities in the profile of antigenic epitopes displayed by melanomasand bystander antigen-presenting cells, and thus may contribute to tumorcell survival in the face of immunological defenses (Haque et al.,2002).

IFI44L was shown to be associated with CDKN2A, a gene associated withcutaneous melanoma and non-melanoma skin cancer and miR-9, which isassociated with nasopharyngeal carcinoma (Gao et al., 2013; Puig-Butilleet al., 2014).

The IFIT1 gene is down-regulated in MCF7 breast cancer cells. Othersreported that the IFIT1 gene was inactivated in hypopharynx cancer (Xuet al., 2013a; Motaghed et al., 2014). Furthermore, miR-9 can modulatethe expression of IFIT1 gene in human cancer cells (Gao et al., 2013).

IFT172 is associated with chemoresistance in gastric cancer (Huang etal., 2014a).

IGHG1 was over-expressed in human pancreatic cancer tissues compared toadjacent non-cancerous tissues. On the contrary, the IGHG1 protein wasdown-regulated in infiltrating ductal carcinomas tissues (Kabbage etal., 2008; Li et al., 2011b). siRNA targeted silencing of IGHG1 was ableto inhibit cell viability and promote apoptosis (Pan et al., 2013).

Researchers have observed expression of IGHG3 in Saudi females affectedby breast cancer. Similarly, gains in copy number as well as elevatedlevels of IGHG3 were detected in African American men suffering fromprostate cancer. Another report showed that IGHG3 expression is found insquamous non-small cell lung cancers, malignant mesothelioma as well ason tumor cells that are sporadically seen in MALT lymphomas and thatshow a propensity for differentiation into plasma cells (Remmelink etal., 2005; Bin Amer et al., 2008; Ledet et al., 2013; Zhang et al.,2013c; Sugimoto et al., 2014).

Recent work has detected rearrangements involving IGHG4 in primarytesticular diffuse large B cell lymphoma (Twa et al., 2015).

Studies have observed down-regulation of IGHM in Chinese patientsaffected by rhabdomyosarcoma. Others have detected expression of IGHM indiffuse large B-cell lymphoma. Another group has found that in diffuselarge B-cell lymphoma the IGHM gene is conserved only on the productiveIGH allele in most IgM+ tumors. In addition, epithelioid angiomyolipomasamples did not show any reactivity for transcription factor binding toIGHM enhancer 3 or transcription factor EB (Kato et al., 2009; Blenk etal., 2007; Ruminy et al., 2011; Liu et al., 2014a).

IMPDH2 over-expression was found in osteosarcoma and human prostatecancer tissues as well as in leukemic cells (Nagai et al., 1991; Zhou etal., 2014b). Inhibitors of IMPDH2 such as tiazofurin and benzamideriboside exhibited a good clinical response in patients with acutemyeloid leukemia and chronic myeloid leukemia in blast crisis (Wright etal., 1996; Jayaram et al., 1999).

INADL is down-regulated in non-small cell lung cancer in response tocisplatin-gemcitabine combination chemotherapy (Ma et al., 2015).

Over-expression of INPPL1 has been observed in breast cancer, non-smallcell lung cancer, hepatocellular carcinoma and laryngeal squamous cellcarcinoma (Prasad et al., 2008b; Zhou et al., 2011; Fu et al., 2013b; Fuet al., 2013c). It has been reported that INPPL1 silencing in breastcancer cells reduces cell proliferation in vitro and cancer growth invivo and inhibits tumor metastases (Prasad et al., 2008a).

The expression of IPP was elevated in human breast tumor samplescompared to non-cancer tissues (Govindaraj et al., 2012).

Several lines of evidence have shown that IQGAP1 is over-expressed invarious tumor types, including colorectal carcinoma, gastric cancer,hepatocellular carcinoma, pancreatic cancer, ovarian cancer andesophageal squamous cell carcinoma (Takemoto et al., 2001; Dong et al.,2006; Hayashi et al., 2010; White et al., 2010; Wang et al., 2013i; Wanget al., 2014i). In addition, high levels of IQGAP1 were correlated withpoor prognosis in ovarian carcinomas and colorectal carcinoma (Dong etal., 2006; Hayashi et al., 2010).

A recent study suggested a genetic association of IRAK2 rs35060588 withcolorectal cancer survival. On the other hand, no mutations were foundin IRAK2 in patients suffering from chronic lymphocytic leukemia(Martinez-Trillos et al., 2014; Wang et al., 2014c). Researchers haveobserved that over-expression of IRAK2 correlated with decreaseddisease-free survival of patients with non-adenocarcinoma (Seol et al.,2014).

IL6 up-regulates IRF9 in prostate cancer cell lines both at the mRNA andprotein levels (Erb et al., 2013). Another study has shown that thatup-regulated IRF9 confers resistance to the anti-microtubule agentpaclitaxel in drug-resistant breast cancer cells (Luker et al., 2001).

Many studies have reported over-expression of ISG15 in several tumors,such as bladder cancer, breast cancer, oral squamous cell carcinoma,cervical cancer and prostate cancer (Andersen et al., 2006; Chi et al.,2009; Kiessling et al., 2009; Rajkumar et al., 2011; Wood et al., 2012;Vincent-Chong et al., 2012). In breast cancer, high ISG15 expression wasassociated with an unfavorable prognosis (Wood et al., 2012).

ISYNA1 is associated with chemotherapy response in cutaneous malignantmelanoma (Azimi et al., 2014). ISYNA1 was shown to be up-regulated inthe human liver carcinoma cell line HepG2 under various conditions (Guanet al., 2003). ISYNA1 inhibition is associated with decreasedproliferation in the SK-N-SH neuroblastoma cell line (Ye and Greenberg,2015).

ITGB2 gene polymorphisms have been associated with colorectal neoplasiaand sporadic infiltrative duct breast carcinoma. Moreover,over-expression of ITGB2 was observed in peripheral blood neutrophils inpatients with advanced epithelial ovarian cancer as well as in leukemia.On the contrary, ITGB2 was absent or only dimly expressed inpromyelocytic leukemia (Phongpradist et al., 2010; Fu et al., 2011; Zhouet al., 2012b; Chang et al., 2013; Bednarska et al., 2016). cIBR-coupledPLGA nanoparticles targeting ITGB2 hold promise as a selective drugdelivery system for leukemia treatment (Chittasupho et al., 2010).

ITGB4 is associated with prostate cancer, gastric cancer, breast cancer,oral squamous cell carcinoma and ovarian cancer and was shown to beup-regulated in pancreatic ductal adenocarcinoma (Chen et al., 2014e;Xin et al., 2014; Zubor et al., 2015; Masugi et al., 2015; Gao et al.,2015; Kawakami et al., 2015). ITGB4 (also called CD104) tends toassociate with the alpha 6 subunit and is likely to play a pivotal rolein the biology of several invasive carcinomas such as esophagealsquamous cell carcinoma, bladder and ovarian carcinoma (Kwon et al.,2013; Pereira et al., 2014; Chen et al., 2014e). A single nucleotidepolymorphism in ITGB4 seems to influence tumor aggressiveness andsurvival and may have prognostic value for breast cancer patients(Brendle et al., 2008).

Over-expression of ITGB8 has been observed in several cancers includinghepatocellular carcinoma, head and neck cancer, some ovarian cancer andmelanoma cell lines as well as primary non-small lung cancer samples andbrain metastases from several epithelial cancers (Liu et al., 2002b;Goodman et al., 2012; Vogetseder et al., 2013). Furthermore, silencingof ITGB8 caused Snail and NF-Î ^(o) B transcriptional activation and MEKand Akt phosphorylation level changes in lung cancer cell lines (Xu andWu, 2012). Knockdown of ITGB8 in PC-3 and 22Rv1 prostate cancer cells invitro resulted in significant reduction of cell migration and invasion(Mertens-Walker et al., 2015). Researchers have found thatover-expression of ITGB8 could be an inducer of gefitinib resistance ofhepatic cancer. ITGB8 might interact with TGF-beta pathway to achieveits anti-gefitinib effects (Wang et al., 2015f).

It has been reported that the expression of ITPR1 is altered intamoxifen resistance breast cancer cell lines (Elias et al., 2015).Researchers have postulated a role for the HIF2alpha/ITPR1 axis inregulating clear cell renal cell carcinomas cell survival. In addition,ITPR1 was significantly correlated with overall survival in breastcancer (Messai et al., 2014; Gu et al., 2016).

Single nucleotide polymorphism in the ITPR2 gene was correlated withrisk of renal cell carcinoma in a Chinese population. Likewise, twocommon variants in linkage disequilibrium, rs718314 and rs1049380 in theITPR2 gene were identified as novel susceptibility loci for renal cellcarcinoma. Moreover, over-expression of ITPR2 was observed in normalacute myeloid leukemia patients compared to healthy persons (Wu et al.,2012d; Shi et al., 2015; Zhang et al., 2016a). In normal acute myeloidleukemia, elevated levels of ITPR2 expression were associated withshorter overall survival and event-free survival (Shi et al., 2015).

Studies have detected expression of JUP in colorectal cancer and lungadenocarcinoma, while a high ITGB4/JUP ratio was found in oral squamouscell carcinoma (Wang and Zheng, 2014; Yang et al., 2012a; Schuetz etal., 2012; Sheng and Zhu, 2014; Nagata et al., 2013).

Over-expression of KARS was found in gastric carcinoma as well astumor-associated inflammatory cells. Moreover, mutations in the KARSgene were identified in patients suffering from colorectal cancer.Others have observed that whole-arm loss of chromosome 16q in breastcancer was related with decreased expression of KARS (Yen et al., 2009;Hungermann et al., 2011; Kim et al., 2014a). It is reported that KARS isinvolved in cell-cell and cell-ECM adhesion during KARS-mediatedmetastasis (Nam et al., 2015).

KCNK15 gene hyper-methylation was found in several cell lines, includingcolon cancer, leukemia, and bladder cancer (Shu et al., 2006).

KDELR1 has a role in tumorigenesis (Yi et al., 2009). Decreased KDELR1levels are found in hepatoma cells (Hou et al., 2015). Down-regulationof KDELR1 is seen in acute myeloid leukemia (Caldarelli et al., 2013).

Over-expression of KDM1A promotes tumor cell proliferation, migrationand invasion and was associated with poor prognosis in NSCLC and HCC (Lvet al., 2012; Zhao et al., 2013d). Elevated expression of KDM1Acorrelates with prostate cancer recurrence and with increased VEGF-Aexpression (Kashyap et al., 2013). Inhibition of KDM1A with acombination of trichostatin A (TSA) and 5-aza-2′-deoxycytidine(decitabine) suppresses the tumorigenicity of the ovarian cancer ascitescell line SKOV3 (Meng et al., 2013).

KDM1B was shown to inhibit cell growth in the lung cancer cell line A549due to its E3 ubiquitin ligase activity (Yang et al., 2015b). KDM1B wasshown to be involved in the regulation of the presumed tumor suppressortissue factor pathway inhibitor-2 (Mino et al., 2014). KDM1B was shownto be up-regulated in breast cancer and amplified and up-regulated inhigh grade urothelial carcinomas (Heidenblad et al., 2008; Katz et al.,2014). KDM1B was shown to play a role in DNA methylation and genesilencing in breast cancer. Inhibition of both KDM1B and DNAmethyltransferase was described as a novel approach for epigenetictherapy of breast cancer (Katz et al., 2014). KDM1B was shown to beassociated with the acquisition of cancer stem cell properties,including self-renewal, clonal formation, and chemotherapy resistance inhyaluronan-CD44v3 activated head and neck cancer (Bourguignon et al.,2012).

Over-expression of KIAA0196 was observed in clinical prostate carcinomasand was also amplified in 30-40% of xenografts and hormone-refractorytumors (Porkka et al., 2004). Amplification of KIAA0196 gene wascorrelated with worse prognosis in high-grade estrogen receptor-negativebreast cancer (Chin et al., 2007). In prostate cancer, KIAA0196 did notseem to have any significant role in growth, anchorage-independentgrowth or invasion in vitro (Jalava et al., 2009).

KIAA1324 is over-expressed in different cancer types including breast,lung, pancreatic and ovarian cancer (Schlumbrecht et al., 2011; Estrellaet al., 2014; Bauer et al., 2004). KIAA1324 shows a tumor suppressorbehavior in gastric cancer where KIAA1324 is down-regulated and this isassociated with poor prognosis (Kang et al., 2015b).

Inhibition of KIF11 was shown to stop growth of the moretreatment-resistant glioblastoma tumor-initiating cells (TICs) as wellas non-TICs and impeded tumor initiation and self-renewal of the TICpopulation (Venere et al., 2015). Targeting KIF11 was also shown toreduce glioma cell invasion and to prolong survival of mice bearingortho-topic glioblastoma (Venere et al., 2015). Thus, KIF11 plays a roleas a driver of invasion, proliferation, and self-renewal in glioblastoma(Venere et al., 2015). Higher expression of mitosis-associated genessuch as KIF11 was shown to be associated with complete response ofhepatocellular carcinomas to trans-arterial chemoembolization treatment(Gaba et al., 2015). Interfering with KIF11 function was described tocause potent inhibition of tumor angiogenesis in experimental tumormodels (Exertier et al., 2013). KIF11 was shown to be down-regulated inbone marrow samples from patients with multiple myeloma and acutemyeloid leukemia (Cohen et al., 2014). Nuclear KIF11 expression wasdescribed as a potential predictive biomarker for docetaxel response inmetastatic castrate-resistant aggressive prostate cancer and as aprognostic biomarker for prostate cancer aggressiveness (Wissing et al.,2014). KIF11 was shown to be essential for tumor cell survival innon-small cell lung cancer and head and neck squamous cell carcinoma andthus may be a potential anti-cancer target (Martens-de Kemp et al.,2013). Up-regulation of KIF11 was shown to be associated with ependymomarecurrence in children (Peyre et al., 2010).

In breast cancer, KIF15 was shown to be over-expressed and to beimmunogenic, as anti-KIF15 antibodies could be isolated from breastcancer patients (Scanlan et al., 2001). Furthermore, KIF15 appears to beimplicated in lung adenocarcinoma (Bidkhori et al., 2013).

Methylation of KIF1A is known to be frequent and higher levels wereshown in thyroid cancer, breast cancer, head and neck squamous cellcarcinoma (Aviles et al., 1991; Hoque et al., 2008; Demokan et al.,2010; Guerrero-Preston et al., 2014). Moreover, KIF1A was found inplasma and saliva of lung cancer and head and neck squamous cellcarcinoma patients compared to controls. These findings suggest that itcould be used as a biomarker for early detection in these disorders(Ostrow et al., 2010). In breast cancer, over-expression of KIF1A wasfound to correlate with chemotherapy resistance in cell lines (De etal., 2009).

Over-expression of KIF20A was detected in pancreatic ductaladenocarcinoma, melanoma, bladder cancer, non-small cell lung cancer andcholangiocellular carcinoma (Imai et al., 2011; Yamashita et al., 2012;Stangel et al., 2015). Recently, it was reported that patients withpancreatic ductal adenocarcinoma vaccinated with a KIF20A-derivedpeptide exhibited better prognosis compared to the control group(Asahara et al., 2013). In addition, silencing of KIF20A resulted in aninhibition of proliferation, motility, and invasion of pancreatic cancercell lines (Stangel et al., 2015).

Fusions of the KIF5B gene and the ret proto-oncogene (RET) have beenobserved in patients suffering from lung cancers, adenocarcinoma andnon-small cell lung cancer (Kohno et al., 2012; Cai et al., 2013b; Qianet al., 2014). KIF5B-RET expression in Ba/F3 cells resulted in oncogenictransformation as determined by interleukin-3 (IL-3)-independent growth(Lipson et al., 2012).

KIFC1 plays a crucial role by the cell division of meiotic cells byfocusing acentrisomal microtubule organizing centers into two spindlepoles. In cancer cells, KIFC1 was shown to be essential for properspindle assembly, stable pole-focusing and survival of cancer cellsindependently from number of formed centrosomes (normal or supernumerarycentrisomes). A constitutive activation of the DNA damage response incancer was shown partially to mediate acentrisomal spindle formation.The dependency of acentrisomal spindle formation from KIFC1 makes KIFC1to the attractive target for cancer therapy. A number of potential KIFC1inhibitors are under current investigation (Li et al., 2015e;Kleylein-Sohn et al., 2012; Wu et al., 2013a; Watts et al., 2013; Zhanget al., 2016b). Furthermore, KIFC1 shows centrosomeclustering-independent pro-proliferative effects which is based on theprotection of survivin from proteasome-mediated degradation (Pannu etal., 2015). KIFC1 expression was shown to be up-regulated in breastcancer, particularly in estrogen receptor negative, progesteronereceptor negative and triple negative breast cancer, and 8 human breastcancer cell lines. In estrogen receptor-positive breast cancer cells,KIFC1 was one of 19 other kinesins whose expression was strongly inducedby estrogen. In breast cancer, the overexpression of KIFC1 and itsnuclear accumulation was shown to correlate with histological grade andpredict poor progression-free and overall survival. In breast cancercell lines, the overexpression of KIFC1 was shown to mediate theresistance to docetaxel. The KIFC1 silencing negatively affected thebreast cancer cell viability (Zou et al., 2014a; Pannu et al., 2015; Deet al., 2009; Li et al., 2015e). KIFC1 was shown to be overexpressed inovarian cancer which was associated with tumor aggressiveness, advancedtumor grade and stage. Thus, KIFC1 may serve as a potential biomarkerthat predicts worse prognosis, poor overall survival and onset ofmetastatic dissemination (Pawar et al., 2014). KIFC1 was identified asone of three genes, whose higher expression in primary NSCLC tumorsindicated the higher risk for development of brain metastasis(Grinberg-Rashi et al., 2009).

KLHL14 is associated with primary central nervous system lymphoma (Vateret al., 2015).

KLHL15 was shown to interact as an E3 ubiquitin ligase adaptor with theprotein phosphatase 2A, a tumor suppressor that was shown to begenetically altered or functionally inactivated in many solid cancers(Oberg et al., 2012; Perrotti and Neviani, 2013).

KLHL7 was shown to be up-regulated in thyroid tumors (Jacques et al.,2005). KLHL7 is associated with lymphocyte-rich classical Hodgkin'slymphoma, follicular lymphoma and diffuse large B-cell lymphoma (Weigertet al., 2012; Trifonov et al., 2013; Nam-Cha et al., 2009).

Several publications have detected over-expression of KLK7 mRNA andprotein in early-stage ovarian tumors, colon cancer, cervical cancer andbreast cancer. Others have observed low levels of KLK7 expression inprostate cancer (Talieri et al., 2004; Walker et al., 2014; Li et al.,2014e; Zhang et al., 2015c; Tamir et al., 2014). In addition, KLK7expression was correlated with poor outcome of patients suffering fromunresectable pancreatic ductal adenocarcinomas and breast cancer(Talieri et al., 2004; Iakovlev et al., 2012). It seems that KLK7induces cancer cell migration, invasiveness and inducesepithelial-mesenchymal transition-like changes in prostate tumor cells(Mo et al., 2010).

KRT14 is highly expressed in various squamous cell carcinomas such asesophageal, lung, larynx, uterine cervical as well as in adenomatoidodontogenic tumor. However, it was absent in small cell carcinoma of theurinary bladder and weak in lung adenocarcinoma, gastric adenocarcinoma,colorectal adenocarcinoma, hepatocellular carcinoma, pancreatic ductaladenocarcinoma, breast infiltrating ductal adenocarcinoma, thyroidpapillary carcinoma and uterine endometrioid adenocarcinoma (Xue et al.,2010; Terada, 2012; Vasca et al., 2014; Hammam et al., 2014; Shruthi etal., 2014). In bladder cancer, KRT14 expression was strongly associatedwith poor survival (Volkmer et al., 2012).

Over-expression of KRT16 was found in basal-like breast cancer celllines as well as in carcinoma in situ. Others did not find significantdifference in immunohistochemical expression of KRT16 betweennon-recurrent ameloblastomas and recurrent ameloblastomas (Joosse etal., 2012; Ida-Yonemochi et al., 2012; Safadi et al., 2016). Inaddition, in silico analyses showed correlation between KRT16 expressionand shorter relapse-free survival in metastatic breast cancer (Joosse etal., 2012).

Over-expression of KRT17 was found in various cancers such as carcinomain situ, squamous cell carcinoma, Ewing sarcoma and epithelial ovariancancer (Mikami et al., 2011; Wang et al., 2013j; Sankar et al., 2013).Furthermore, high levels of KRT17 expression were significantlyassociated with poor survival of squamous cell carcinoma, epithelialovarian cancer, breast cancer and pancreatic cancer (van de Rijn et al.,2002; Sarbia et al., 2007; Wang et al., 2013j; Escobar-Hoyos et al.,2014). Researchers have demonstrated that KRT17 expression promotessquamous cell carcinoma cell growth and cell size but does not affectcell migration (Mikami et al., 2015).

L3MBTL4 was shown to be targeted by deletion, breakage and mutations inbreast cancer. It was also shown to be down-regulated in breast cancerand thus may be a potential tumor suppressor gene (Addou-Klouche et al.,2010). L3MBTL4 resides in a chromosome region that was shown to befrequently deleted in a rare subtype with poor prognosis of acutemyeloid leukemia (Veigaard et al., 2011).

Studies have shown that the level of LAMA5 was elevated in basal cellcarcinoma, cervical cancer and breast carcinoma (Simonova et al., 2015;Scotto et al., 2008; Mostafa et al., 2010; Georgiou et al., 2013).

LAT2 expression is able to separate T lineage leukemias into twosubgroups, while others have reported that LAT2 acts as a tumorsuppressor able to enhance the proximal signaling of leukemic blasts(Svojgr et al., 2009; Svojgr et al., 2012). In addition, loss of LAT2suppressed AKT activation, decreased cell proliferation and increasedcell sensitivity to drugs such as ODPC, perifosine and arsenic trioxide(Thome et al., 2012).

The C/C(-13910) genotype of the LCT gene is significantly associatedwith increased risk of colorectal cancer in the Finnish population butnot in the British or Spanish subjects (Fairfield et al., 2004;Rasinpera et al., 2005; Travis et al., 2013). A decreased survival ratewas observed in patients suffering from colorectal cancer with LCTC/C(-13910) genotype (Bacsi et al., 2008).

Several studies have observed high levels or ineffectively regulatedLDLR expression in various types of cancer, for instance over-expressionof LDLR was reported in lung adenocarcinoma cell line, prostate cancercells as well as human colorectal cancer biopsies. In contrast,decreased feedback regulation of LDLR has been reported in leukemiccells from acute myelogenous patients (Gueddari et al., 1993; Tatidis etal., 1997; Lum et al., 1999; Chen and Hughes-Fulford, 2001).

Studies have detected up-regulation of mRNA and protein level ofLGALS3BP in colorectal carcinoma tissues as well as in lung cancer(Ozaki et al., 2004; Iacovazzi et al., 2010; Wu et al., 2008). Elevatedlevels of LGALS3BP were correlated with poor prognosis in diffuse largeB-cell lymphomas (Kim et al., 2008d). Moreover, in lung cancer LGALS3BPis involved in cancer metastasis by increasing adhesiveness of cancercells (Ozaki et al., 2004).

LGR6 is associated with triple-negative breast cancer, gastric cancerand colon cancer (Gong et al., 2012; Rocken, 2013; Purrington et al.,2014). LGR6 was shown to be up-regulated in gastric cancer (Steffen etal., 2012). LGR6 is associated with local tumor growth and patientsurvival in gastric cancer (Steffen et al., 2012).

LLGL1 expression is reduced or absent in breast cancers, lung cancers,prostate cancers, ovarian cancers, colorectal cancers, melanomas,endometrial cancers and hepatocellular carcinomas (Schimanski et al.,2005; Kuphal et al., 2006; Tsuruga et al., 2007; Lu et al., 2009; Songet al., 2013b). It seems that LLGL1 inhibits proliferation and promotesapoptosis in the esophageal carcinoma cell line through amitochondria-related pathway. Furthermore, reduced LLGL1 transcriptionhas been linked with lymph node metastases, whereas over-expression ofLLGL1 resulted in increased cell adhesion and decreased cell migration(Schimanski et al., 2005; Kuphal et al., 2006; Tsuruga et al., 2007;Song et al., 2013b).

Expression of LMNB1 is reduced in colon cancer and gastric cancer,whereas it is over-expressed in prostate cancer, hepatocellularcarcinoma and pancreatic cancer (Moss et al., 1999; Lim et al., 2002;Coradeghini et al., 2006; Li et al., 2013a). In hepatocellularcarcinoma, the expression level of LMNB1 correlated positively withtumor stage, tumor sizes and number of nodules. These findings suggestthat LMNB1 could be used to detect early stages of hepatocellularcarcinoma (Sun et al., 2010).

The cancer/testis antigen family 45 was shown to be frequently expressedin both cancer cell lines and lung cancer specimens (Chen et al., 2005).CT45 genes were shown to be potential prognostic biomarkers andtherapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

LPCAT2 is associated with prostate cancer (Williams et al., 2014).LPCAT2 was shown to be up-regulated in breast cancer, cervical cancerand colorectal cancer (Agarwal and Garg, 2010). LPCAT2 expression isassociated with patient outcome in prostate cancer (Williams et al.,2014).

Inhibition of LRBA expression by RNA interference, or by adominant-negative mutant, resulted in the growth inhibition of cancercells. These findings imply that deregulated expression of LRBAcontributes to the altered growth properties of a cancer cell (Wang etal., 2004).

LTBP2 has been shown to be up-regulated in hepatocellular carcinoma,pancreatic ductal adenocarcinoma, whereas in esophageal squamous cellcarcinoma cell lines and tumor tissues the expression of LTBP2 wasdown-regulated (Chan et al., 2011; Turtoi et al., 2011; Cho et al.,2016). In hepatocellular carcinoma, high levels of LTBP2 weresignificantly correlated with shorter time to tumor recurrence.Similarly, elevated levels of LTBP2 were associated with poor outcomefor ER(−)/PR(−) breast cancer patients (Naba et al., 2014; Cho et al.,2016).

LTN1, also known as ZNF294, encodes the listerin E3 ubiquitin proteinligase 1 and is located on chromosome 21q22.11 (RefSeq, 2002). LTN1 isassociated with high level microsatellite instability in colorectalcancer (Reuschenbach et al., 2010).

LURAP1 was shown to be a NF-kB activator which may be a candidate genefor regulating the function of dendritic cells to resisttumor-associated factor-mediated dysfunction (Jing et al., 2010).

It has been reported that the LYST gene is localized within the copynumber aberration regions in multiple myeloma (Ivyna Bong et al., 2014).

Researchers have reported expression of M6PR in colon carcinoma celllines as well as in choriocarcinoma cells (Braulke et al., 1992;O'Gorman et al., 2002). In breast cancer, low-level expression of M6PRwas associated with poor patient prognosis (Esseghir et al., 2006).Furthermore, over-expression of M6PR resulted in a decreased cellulargrowth rate in vitro and decreased tumor growth in nude mice (O'Gormanet al., 2002).

MACF1 is associated with colorectal cancer, renal cell carcinoma andlung adenocarcinoma (Bidkhori et al., 2013; Arai et al., 2014; Kim etal., 2015b). MACF1 was shown to be associated with neuroblastoma in theCLB-Bar cell line (Schleiermacher et al., 2005).

Over-expression of MADD has been found in many types of human tumors,including non-small cell lung cancer, lung adenocarcinoma, squamous cellcarcinoma, thyroid cancer, breast cancer and ovarian cancer (Subramanianet al., 2009; Li et al., 2011a; Wei et al., 2012; Bi et al., 2013;Turner et al., 2013). Researchers have demonstrated that elevated levelsof MADD in the A549 cells inhibited apoptosis and increased survival,while knock-down of MADD promoted apoptosis and reduced cellproliferation (Wei et al., 2012; Bi et al., 2013). Additionally, MADDfunction is regulated by PTEN-PI3K-Akt signaling pathway (Jayarama etal., 2014).

MAGEA4 was described as a cancer testis antigen which was found to beexpressed in a small fraction of classic seminomas but not innon-seminomatous testicular germ cell tumors, in breast carcinoma,Epstein-Barr Virus-negative cases of Hodgkin's lymphoma, esophagealcarcinoma, lung carcinoma, bladder carcinoma, head and neck carcinoma,and colorectal cancer, oral squamous cell carcinoma, and hepatocellularcarcinoma (Ries et al., 2005; Bode et al., 2014; Li et al., 2005;Ottaviani et al., 2006; Hennard et al., 2006; Chen et al., 2003). MAGEA4was shown to be frequently expressed in primary mucosal melanomas of thehead and neck and thus may be a potential target for cancer testisantigen-based immunotherapy (Prasad et al., 2004). MAGEA4 was shown tobe preferentially expressed in cancer stem-like cells derived from LHK2lung adenocarcinoma cells, SW480 colon adenocarcinoma cells and MCF7breast adenocarcinoma cells (Yamada et al., 2013). Over-expression ofMAGEA4 in spontaneously transformed normal oral keratinocytes was shownto promote growth by preventing cell cycle arrest and by inhibitingapoptosis mediated by the p53 transcriptional targets BAX and CDKN1A(Bhan et al., 2012). MAGEA4 was shown to be more frequently expressed inhepatitis C virus-infected patients with cirrhosis and late-stagehepatocellular carcinoma compared to patients with early stagehepatocellular carcinoma, thus making the detection of MAGEA4transcripts potentially helpful to predict prognosis (Hussein et al.,2012). MAGEA4 was shown to be one of several cancer/testis antigens thatare expressed in lung cancer and which may function as potentialcandidates in lung cancer patients for polyvalent immunotherapy (Kim etal., 2012b). MAGEA4 was described as being up-regulated in esophagealcarcinoma and hepatocellular carcinoma (Zhao et al., 2002; Wu et al.,2011c). A MAGEA4-derived native peptide analogue called p286-1Y2L9L wasdescribed as a novel candidate epitope suitable to develop peptidevaccines against esophageal cancer (Wu et al., 2011c). Several membersof the MAGE gene family, including MAGEA4, were shown to be frequentlymutated in melanoma (Caballero et al., 2010).

The expression of MAGEA8 was detected in various tumors such ashepatocellular carcinoma, colorectal carcinoma and ovarian cancer(Hasegawa et al., 1998; Tahara et al., 1999; Eng et al., 2015).Furthermore, over-expression of MAGEA8 was associated with poorprogression free survival in patients with high CD3 tumors (Eng et al.,2015).

MAGEC3 was described as being expressed only in testis and in tumors ofdifferent histological origins. Thus, MAGEC3 could be a target forcancer immunotherapy (Lucas et al., 2000).

Flavopiridol induces an inhibition of human tumor cell proliferation andthe down-regulation of MAGEF1 in different human tumor cell lines (Lu etal., 2004). MAGEF1 is significantly over-expressed in colorectal cancertissues (Chung et al., 2010).

MAGT1 was shown to be associated with a predisposition to lymphoma(Chaigne-Delalande et al., 2013).

A polymorphism in the MANBA gene was associated with the risk ofcolorectal cancer in the Swedish population, but not in the Chinesepopulation. Others have observed elevated levels of MANBA in esophagealcancer (Sud et al., 2004; Gao et al., 2008).

MCM10 was show to be up-regulated in esophageal squamous cell carcinomaand cervical cancer (Das et al., 2013a; Lu et al., 2014b). MCM10expression is associated with tumor grade in glioma and cervical cancer(Das et al., 2013a; Hua et al., 2014). MCM10 is associated with earlygastric cancer, breast cancer and lung cancer (Wu et al., 2012a; Kang etal., 2013). MCM10 may be used as a biomarker for esophageal squamouscell carcinoma (Lu et al., 2014b).

MCM2 has been shown to be the most sensitive marker of proliferation andprognosis in early breast cancer, renal cell carcinomas, esophageal andlaryngeal squamous cell carcinoma and oligodendroglioma of the brain(Wharton et al., 2001; Going et al., 2002; Rodins et al., 2002; Gonzalezet al., 2003; Cai et al., 2012; Joshi et al., 2015).

Researchers have observed lower levels of MDH2 expression inparagangliomas. On the other hand, others reported over-expression ofMDH2 in gastric cancer as well as in prostate cancer cell lines and inpatient specimens (Liu et al., 2013b; Yao et al., 2015; Cascon et al.,2015). In gastric cancer, elevated levels of MDH2 were associated withdepth of invasion, lymph node metastasis, distant metastasis and TNMstaging (Yao et al., 2015). MDH2 has been shown to be involved in thedevelopment of doxorubicin-resistant uterine cancer, while others haverevealed that MDH2 induces prostate cancer resistance todocetaxel-chemotherapy via JNK pathway (Liu et al., 2013b; Lo et al.,2015).

MEMO1 is associated with buccal mucosa squamous cell carcinoma (Shah etal., 2013). MEMO1 is associated with migration, invasion and lungmetastasis of breast cancer (MacDonald et al., 2014). MEMO1 was shown tobe up-regulated in the pancreatic cancer cell line PaCa (Kalinina etal., 2010). MEMO1 is a prognostic factor of early distant metastasis ofprimary breast cancer (MacDonald et al., 2014).

Over-expression of MFGE8 has been found in various tumors includingbreast cancer, malignant melanoma, bladder tumors, ovarian cancer andsquamous cell carcinoma (Jinushi et al., 2008; Sugano et al., 2011;Carrascosa et al., 2012; Tibaldi et al., 2013; Yamazaki et al., 2014).It seems that MFGE8 is able to enhance tumorigenicity and metastaticcapacity via Akt-dependent and Twist-dependent pathways (Jinushi et al.,2008).

MGA was shown to be mutated in lung adenocarcinoma (2014). MGA was shownto be inactivated in non-small cell lung cancer, small cell lung cancerand chronic lymphocytic leukemia (De et al., 2013; Romero et al., 2014).

MGRN1 is associated with osteosarcoma (Man et al., 2004).

MKI67IP was shown to be trans-activated by c-Myc and silencing ofMKI67IP resulted in inhibition of cell proliferation. Thus, MKI67IP mayplay a role in cancer (Pan et al., 2015).

A study has shown that MKKS is up-regulated in tumors with synchronousadenoma (Kim et al., 2008a).

Methylation and over-expression of MLF1 has been linked with lungsquamous cell carcinoma, myeloid leukemia and gastric cancer. Genomicprofiling studies have identified MLF1 gene in human esophageal cancer(Shi et al., 2012; Matsumoto et al., 2000; Sun et al., 2004b; Chen etal., 2008). In gastric cancer, methylation of MLF1 gene was positivelyassociated with the number of lymph node metastasis. However, it did nothave any prognostic value for gastric cancer patients (Shi et al.,2012). It is reported that MLF1 promotes prostate cancer cellproliferation, colony formation and significantly inhibits apoptosis(Zhang et al., 2015h).

MMP7 is frequently over-expressed in human cancer tissue, includingcolorectal cancer, metastatic lung carcinoma and gastric cancer and isassociated with cancer progression and metastasis formation (Ii et al.,2006; Sun et al., 2015b; Han et al., 2015a; Long et al., 2014). MMP7 hasbeen shown to play important tumor promoting roles, like degradation ofextracellular matrix proteins, activation of tumor cell proliferation byincreasing the bioavailability of insulin-like growth factor andheparin-binding epidermal growth factor and induction of apoptosis intumor-adjacent cells by cleaving membrane bound Fas ligand (Ii et al.,2006).

MRPL11 was shown to be differently expressed in squamous cell carcinomacompared to normal tissue (Sugimoto et al., 2009). MRPL11 expression isassociated with progression free survival and metastatic phenotypes ofcervical cancer (Lyng et al., 2006).

Several studies have reported associations between MSH2 gene methylationand various malignancies such as hepatocellular carcinoma, acutelymphoblastic leukemia, clear cell renal cell carcinoma and esophagealsquamous cell carcinoma. On the contrary, promoter hyper-methylation ofMSH2 in sporadic colorectal cancer was a rare event (Vlaykova et al.,2011; Ling et al., 2012; Hinrichsen et al., 2014; Wang et al., 2014a;Yoo et al., 2014). Recent work has demonstrated that cisplatin couldup-regulate the expression of MSH2 by down-regulating miR-21 to inhibitA549 cell proliferation (Zhang et al., 2013e).

In mesothelioma, it has been shown that MSLN induces tumor cell invasionby increasing MMP-9 secretion (Servais et al., 2012). Severalpublications have shown over-expression of MSLN in various types ofcancer such as mesothelioma, triple negative breast carcinomas,pancreatic, ovarian and lung adenocarcinomas (Chang and Pastan, 1996;Argani et al., 2001; Ho et al., 2007; Tozbikian et al., 2014).

Loss of MTAP activity was observed in many tumors such as breast cancer,leukemia, glioblastoma, non-small cell lung cancer and bladder cancer.In addition, promoter hyper-methylation is thought to be thepreponderant inactivating mechanism in MTAP-deficient hepatocellularcarcinomas (Nobori et al., 1991; Smaaland et al., 1987; Kamatani andCarson, 1980; Stadler et al., 1994; Nobori et al., 1993; Hellerbrand etal., 2006). MTAP re-expression in MTAP-deficient myxofibrosarcoma celllines inhibited cell migration, invasion, proliferation,anchorage-independent colony formation and down-regulated cyclin D1 (Liet al., 2014a).

MTBP was shown to be down-regulated in hepatocellular carcinoma (Bi etal., 2015). MTBP was shown to be up-regulated in breast cancer andlymphomas (Grieb et al., 2014; Odvody et al., 2010). MTBP was shown tobe negatively correlated with capsular/vascular invasion and lymph nodemetastasis in hepatocellular carcinoma (Bi et al., 2015). MTBP isassociated with patient survival in breast cancer and head and necksquamous cell carcinoma (Iwakuma and Agarwal, 2012; Grieb et al., 2014).MTBP may be a potential biomarker for cancer progression in osteosarcoma(Agarwal et al., 2013).

MTCH1 is associated with 5-fluorouracil resistance in ContinB andContinD colon cancer cell lines (De Angelis et al., 2006).

MTHFD2 was shown to be up-regulated in Burkitt's lymphoma, diffuse largecell lymphoma, breast cancer and in the saPC-3 prostate cancer cell line(Liu et al., 2014b; Patrikainen et al., 2007; Tedeschi et al., 2015).MTHFD2 expression is correlated with tumor size, histological grade,lymph node metastasis and distant metastases in breast cancer (Liu etal., 2014b). MTHFD2 is associated with poor survival in breast cancerand greater cancer susceptibility and survival in bladder cancer(Nilsson et al., 2014; Andrew et al., 2009). MTHFD2 is a prognosticfactor in breast cancer (Liu et al., 2014b).

Over-expression of MTOR signaling has been linked with poor clinicaloutcome in various types of cancers such as renal, lung, breast,laryngeal squamous cell carcinoma, neuroendocrine tumors, biliary tractadenocarcinoma, colorectal, cervical, ovarian, esophageal cancers,malignant melanoma and head and neck squamous cell carcinoma (Faried etal., 2006; Hou et al., 2007; Liu et al., 2007; Molinolo et al., 2007;Karbowniczek et al., 2008; Faried et al., 2008; Shao et al., 2014).Researchers have revealed that MTOR gene knockdown via lentivirusmediated MTOR specific shRNA resulted in a significant decrease in theviability and growth of prostate cancer cells (Du et al., 2014b).

Researchers found a significant association of polymorphisms in the MTRgene with breast cancer, multiple myeloma and squamous cell carcinoma ofthe head and neck (Zhang et al., 2005b; Kim et al., 2007; Cui et al.,2012; Lopez-Cortes et al., 2013; Hosseini, 2013; Yang et al., 2014a).

MTX2 is associated with discrimination of patient prognosis among acutemyelogenous leukemia subgroups (Vey et al., 2004).

MUC1 was up-regulated in several tumors such as colorectal cancer,breast cancer, lung cancer and esophageal adenocarcinoma (Khodarev etal., 2009; Gronnier et al., 2014; Kesari et al., 2015). In pancreaticcancer, MUC1 affects cell proliferation, migration and invasion bytargeting certain signaling pathways such as p42-44 MAPK, Akt, Bcl-2 andMMP13. Others have observed that elevated levels of MUC1 in B116 andB16BL6 murine melanoma cells mediates up-regulation of Aktphosphorylation (Trehoux et al., 2015; Wang et al., 2015h).Over-expression of MUC1 has been shown to decrease translocation of12-catenin into the nucleus, reduce the activity of T cell factor andinhibit the expression of cyclin D1 and c-Myc (Wang et al., 2013e).

MUC16 was initially recognized to be over-expressed in ovarian cancer.It can be detected in the serum of ovarian cancer patients and is anestablished biomarker for this cancer type. Furthermore, MUC16over-expression has been reported in pancreatic and breast cancer.Cancer patients carrying elevated levels of MUC16 exhibit higherlikelihood of tumor recurrence (Haridas et al., 2014).

MUC20 was described as a prognostic molecular biomarker which isup-regulated in some epithelial tumors (Wang et al., 2015b). MUC20expression in combination with MUC13 expression was shown to be apotential prognostic marker for patients with esophageal squamous cellcarcinoma, who received neoadjuvant chemotherapy followed by surgery(Wang et al., 2015b). MUC20 was shown to be up-regulated in colorectalcancer and endometrial cancer (Chen et al., 2013a; Xiao et al., 2013).MUC20 expression was shown to be associated with recurrence and pooroutcome in colorectal cancer. Disease-free survival and overall survivalwere significantly worse upon up-regulation of MUC20 (Xiao et al.,2013). MUC20 was shown to be a prognostic factor for poor survival whichis also associated with cell growth, migration, and invasion inendometrial cancer (Chen et al., 2013a). MUC20 might play a role intumorigenesis of carcinosarcomas (Vekony et al., 2009).

MUC5AC is de-regulated in a variety of cancer types includingcolorectal, gastric, lung and pancreatic cancer. Depletion or lowexpression in colorectal and gastric tumors is associated with a moreaggressive behavior and poor prognosis. Over-expression in lung cancerresults in an increased likelihood of recurrence and metastases(Yonezawa et al., 1999; Kocer et al., 2002; Kim et al., 2014b; Yu etal., 1996). MUC5AC expression is regulated by different pathways andtranscription factors including Sp1, PKC/ERK/AP-1, PKC/JNK/AP-1, CREB,NF-kappaB and II-1 beta/EGFR/Akt/GK-3beta/beta-catenin (Kato et al.,2006; Raja et al., 2012; Chen et al., 2014h).

MUC5B is over-expressed in different cancer entities includingcolorectal, lung and breast cancer and is associated with tumorprogression (Sonora et al., 2006; Valque et al., 2012; Walsh et al.,2013; Nagashio et al., 2015). MUC5B can be repressed under the influenceof methylation and can be up-regulated by ATF-1, c-Myc, NFkappaB, Sp1,CREB, TTF-11 and GCR (Perrais et al., 2001; Van, I et al., 2000).

MVP is highly expressed in several central nervous system tumors (Yanget al., 2012b). MVP is highly expressed in cancer, and in severalchemoresistant cancer cell lines (Szaflarski et al., 2011; Mossink etal., 2003). MVP expression level increases with age and facilitatesapoptosis resistance (Ryu and Park, 2009).

Allelic gene expression of MX2 following lipopolysaccharide stimulationhas been shown in hepatocellular carcinoma cells. Furthermore, singlenucleotide polymorphism in the MX2 gene was significantly associatedwith multiple primary melanoma (Park et al., 2014; Gibbs et al., 2015).

MYCBP was shown to be up-regulated in colon carcinoma cells and the oralcancer cell lines Hep-2, SSC-9 and Tu-177 (Rey et al., 1999; Jung andKim, 2005). MYCBP is associated with chemosensitivity inoligodendroglial tumors (Shaw et al., 2011). MYCBP was shown to beassociated with cancer cell survival during limited glucose and oxygenavailability in the breast cancer cell line MCF-7 (Sedoris et al.,2010). MYCBP was shown to be differentially expressed in chronic myeloidleukemia (Pizzatti et al., 2006).

MYO1G was shown to be important for cell survival and lysosomalstability in the breast cancer cell line MCF7 (Groth-Pedersen et al.,2012).

NAF1 was shown to interact with GRIM-1, a potential co-tumor suppressorin the prostate (Nallar et al., 2011).

Polymorphisms of NAMPT gene were linked with the risk of developingesophageal squamous cell carcinoma as well as bladder cancer. Moreover,elevated levels of NAMPT were reported in colorectal, breast, prostatic,gastric, thyroid, ovarian and pancreatic cancers (Shackelford et al.,2010; Dalamaga, 2012; Zhang et al., 2014c; Zhang et al., 2015b;Sawicka-Gutaj et al., 2015). Furthermore, single nucleotidepolymorphisms of NAMPT gene were significantly correlated withrecurrence-free survival for total bladder cancer patients andnon-muscle-invasive bladder cancer patients (Zhang et al., 2014c).

NAPRT1 was shown to be associated with cancer. It was also shown thatmutations that decrease NAPRT1 expression can predict usefulness ofnicotinic acid in tumor treatments with NAMPT inhibitors (Duarte-Pereiraet al., 2014). NAPRT1 expression was shown to be lost in many cancertypes due to promoter hyper-methylation, resulting in inactivation ofone of two NAD salvage pathways. Co-administration of a NAMPT inhibitorblocking the second NAD salvage pathway resulted in synthetic lethality.Thus, NAPRT1 provides a novel predictive biomarker for NAMPT inhibitors(Shames et al., 2013). NAPRT1 was described to be lost in a highfrequency of glioblastomas, neuroblastomas, and sarcomas and may beassociated with tumor apoptosis (Cerna et al., 2012). NARPT1 was shownto be down-regulated in Hodgkin's lymphoma (Olesen et al., 2011).

NAT8L expression is elevated in approximately 40% of adenocarcinoma andsquamous cell carcinoma cases. The over-expression leads to elevatedN-acetylaspartate levels in the blood of NSCLC patients presenting apotential biomarker for early lung-cancer detection (Lou et al., 2016).

NBEAL2 deficiency is associated with protection against cancermetastasis in mice (Guerrero et al., 2014). NBEAL2 is part of a set ofbiomarkers for stage discrimination in ovarian cancer (Kashuba et al.,2012).

NCAPD2 over-expression was found in the development of ovarian cancertogether with its amplification and mutation during tumor progression(Emmanuel et al., 2011).

NCAPD3 is a potential biomarker for subtype-1 prostate cancer and forpostoperative biochemical recurrence in prostate cancer (Jung et al.,2014; Lapointe et al., 2008).

NCAPG is down-regulated in patients with multiple myeloma, acute myeloidleukemia, and leukemic cells from blood or myeloma cells (Cohen et al.,2014). NCAPG may be a multi-drug resistant gene in colorectal cancer (Liet al., 2012a). NCAPG is highly up-regulated in the chromophobe subtypeof human cell carcinoma but not in conventional human renal cellcarcinoma (Kim et al., 2010). Up-regulation of NCAPG is associated withmelanoma progression (Ryu et al., 2007). NCAPG is associated with uvealmelanoma (Van Ginkel et al., 1998). NCAPG shows variable expression indifferent tumor cells (Jager et al., 2000).

NCKAP1L over-expression was linked with poor outcome in chroniclymphocytic leukemia. On the other hand, down-regulation of NCKAP1L inpatient chronic lymphocytic leukemia cells resulted in a significantincrease in their susceptibility to fludarabine-mediated killing (Joshiet al., 2007).

The non-synonymous single-nucleotide polymorphism NEK10-L513S at 3p24was shown to be associated with breast cancer risk (Milne et al., 2014).Single-nucleotide polymorphisms in SLC4A7/NEK10 in BRCA2 carriers wereshown to be associated with ER-positive breast cancer (Mulligan et al.,2011). NEK10 was described as being implicated in DNA damage response(Fry et al., 2012). NEK10 was described as a mediator of G2/M cell cyclearrest which is associated with the MAPK/ERK signaling pathway membersERK1/2, Raf-1 and MEK1 (Moniz and Stambolic, 2011).

NFATC2 has been shown to be expressed in human cancers, such as breastcancer and lung cancer. In addition, chromosomal translocation of NFATC2and in-frame fusion with the EWSR1 oncogene have been found in Ewingsarcomas. Moreover, the NFATC2 gene was highly amplified in pancreaticcancer (Holzmann et al., 2004; Yiu and Toker, 2006; Szuhai et al., 2009;Liu et al., 2013a). In breast cancer, NFATC2 is able to induce invasionthrough the induction of COX-2. Others have reported that NFATC2increases invasion of breast cancer cells via a LCN2/TWEAKR/TWEAK axis(Yiu and Toker, 2006; Gaudineau et al., 2012).

Loss of NFE2L3 predisposes mice to lymphoma development. Others haveobserved high levels of NFE2L3 in colorectal cancer cells, whereasaberrant expression of NFE2L3 was found in Hodgkin lymphoma.Furthermore, NFE2L3 exhibited hyper-methylation in ER positive tumors(Kuppers et al., 2003; Chevillard et al., 2011; Palma et al., 2012;Rauscher et al., 2015).

Elevated levels of NHP2L1 were found in lung tumors containingneuroendocrine elements as well as in small cell lung cancer (Jensen etal., 1994; Harken et al., 1999).

NLRC3 was shown to be down-regulated in colorectal cancer, anddown-regulation was correlated with cancer progression (Liu et al.,2015d). NLRC3 was described as a potential negative regulator ofinflammatory responses which interacts with different inflammasomecomponents, such as caspases 1 and 5 (Gultekin et al., 2015).

NOA1 over-expression was shown to induce apoptosis in the human mammaryadenocarcinoma cell line MCF-7 by increasing mitochondrial proteintyrosine nitration and cytochrome c release (Parihar et al., 2008a).NOA1 was shown to regulate apoptosis of human neuroblastoma cells(Parihar et al., 2008b).

NOD2 is associated with colorectal cancer, risk of gastric cancer, MALTlymphoma, breast cancer, lung cancer, laryngeal cancer and prostatecancer (Kang et al., 2012; Liu et al., 2014c; Castano-Rodriguez et al.,2014; Ahangari et al., 2014). NOD2 is associated with lymph nodemetastasis in urothelial bladder cancer (Guirado et al., 2012). NOD2gene polymorphisms may be associated with altered risk of testicular,liver, gallbladder, biliary tract, pancreatic, small bowel, kidney andskin cancer, non-thyroid endocrine tumors, lymphoma and leukemia(Kutikhin, 2011).

NPLOC4 was shown to be associated with p97 and Ufd1 in a complexmediating the alternative NF-kB pathway, which has been implicated incancer (Zhang et al., 2015o).

NR4A2 is highly expressed in several cancers such as bladder, colorectalcancer and gastric cancer. In contrast, down-regulation of NR4A2expression was observed in breast cancer compared to normal breasttissues (Holla et al., 2006; Inamoto et al., 2008; Llopis et al., 2013;Han et al., 2013). In nasopharyngeal carcinoma, high cytoplasmicexpression of NR4A2 was significantly correlated with tumor size, lymphnode metastasis and clinical stage. In addition, patients with highercytoplasmic NR4A2 expression exhibited a significantly lower survivalrate compared to those with lower cytoplasmic NR4A2 expression (Wang etal., 2013f).

siRNAs targeting MAPK inhibit cervical cancer cell line growth and leadto a down-regulation of NUP188 (Huang et al., 2008; Yuan et al., 2010).NUP188 seems to be a target of the tumor suppressor gene BRCA1 in breastcancer (Bennett et al., 2008). NUP188 is required for the chromosomealignment in mitosis through K-fiber formation and recruitment of NUMAto the spindle poles (Itoh et al., 2013).

NUP205 is stabilized by TMEM209. This interaction is a critical driverfor lung cancer proliferation (Fujitomo et al., 2012).

NUP62 is associated with drug resistance in cultured high-grade ovariancarcinoma cells (Kinoshita et al., 2012).

Over-expression of OPA1 was detected in oncocytic thyroid tumors as wellas lung adenocarcinoma (Fang et al., 2012; Ferreira-da-Silva et al.,2015). Others reported that hepatocellular carcinoma cells can besensitized to sorafenib-induced apoptosis by OPA1 siRNA knockdown.Furthermore, silencing of OPA1 expression resulted in reduced cisplatinresistance, increased release of cytochrome c and activation ofcaspase-dependent apoptotic pathway (Fang et al., 2012; Zhao et al.,2013b).

Elevated levels of ORC2 have been observed in metastatic clear-cellrenal-cell carcinoma specimens (Tan et al., 2008). Researchers havedemonstrated that pancreatic cancer cells expressing the Plk1non-phosphorylatable mutant of ORC2 are more sensitive to gemcitabinetreatment (Song et al., 2013a).

OSBPL10 was shown to be an oncogene mutated in breast cancer (Pongor etal., 2015). OSBPL10 was shown to be a target of aberrant somatichyper-mutation associated with primary central nervous system lymphoma(Vater et al., 2015).

PAK6 was shown to be up-regulated in colon cancer tissues and cell linesand hepatocellular carcinoma (Chen et al., 2014b; Tian et al., 2015).PAK6 was shown to be down-regulated in clear cell renal cell carcinoma(Liu et al., 2014e). PAK6 was shown to promote chemoresistance andprogression in colon cancer and motility and invasion of prostate cancercells in the cell line LNCap (Liu et al., 2013c; Chen et al., 2015b).PAK6 is associated with prostate cancer (Zapatero et al., 2014). PAK6 isassociated with unfavorable overall survival and recurrence-freesurvival in clear cell renal cell carcinoma, poor prognosis inhepatocellular carcinoma and drug (gefitinib) resistance in head andneck cancer cell lines (Chen et al., 2014b; Liu et al., 2014e; Hickinsonet al., 2009). PAK6 is a prognostic biomarker for adjuvant 5-FUchemotherapy in stage II and III colon cancer, overall and disease-freesurvival in colon cancer and overall survival as well as recurrence-freesurvival in clear cell renal cell carcinoma after nephrectomy (Liu etal., 2014e; Chen et al., 2015b). PAK6 may be a useful marker todistinguish uterine cervical adenocarcinoma from uterine cervicalsquamous cell carcinoma (Lee et al., 2010).

PARD6B was shown to be a novel candidate target gene of p53 (Garritanoet al., 2013). PARD6B was shown to be up-regulated in breast cancer celllines (Cunliffe et al., 2012). PARD6B was shown to play a role inmorphogenesis of the human epithelial colorectal adenocarcinoma cellline Caco-2 (Durgan et al., 2011). PARD6B was shown to be regulated bythe oncogene steroid receptor coactivator-3 in the breast cancer cellline MCF-7 (Labhart et al., 2005).

PARP10 was shown to be associated with apoptosis, NF-kB signaling, andDNA damage repair and might have a function in cancer biology (Kaufmannet al., 2015). PARP10 was shown to be a regulator of NF-kB signaling(Verheugd et al., 2013). PARP10 was shown to interact with theproto-oncogene c-Myc (Yu et al., 2005).

PARP14 is one factor that mediates proliferation, chemo-resistance andsurvival of metastatic prostate cancer cells (Bachmann et al., 2014).PARP14 is highly expressed in myeloma plasma cells and associated withdisease progression and poor survival. PARP14 is critically involved inJNK2-dependent survival. PARP14 was found to promote the survival ofmyeloma cells by binding and inhibiting JNK1 (Barbarulo et al., 2013).

Researchers have detected elevated levels of mRNA and protein of PARP3in primary glioblastoma tissues. Another group found down-regulation ofPARP3 in breast cancer as well as in non-small cell lung cancer (Friaset al., 2008; Bieche et al., 2013; Quan et al., 2015a). Silencing ofPARP3 gene resulted in decreased cell proliferation and inhibition oftumor growth in vivo in a glioblastoma xenograft mouse model. In lungcancer cell lines, miR-630 reduced apoptosis by downregulating severalapoptotic modulators such as PARP3 (Cao et al., 2014; Quan et al.,2015a).

PARPBP was shown to be up-regulated in pancreatic cancer (O'Connor etal., 2013). PARPBP was shown to be potentially associated with cervicalcancer in the HeLa cell line (van et al., 2012).

PAWR has been shown to be down-regulated in many cancers including,breast cancer, lymphoma and renal cell carcinoma (Cook et al., 1999;Boehrer et al., 2001; Nagai et al., 2010). In addition, reducedexpression of PAWR was correlated with poor prognosis in breast cancerpatients (Nagai et al., 2010; Alvarez et al., 2013). Phosphorylation ofPAWR by Akt results in its binding and sequestration in the cytoplasmhence preventing apoptosis in prostate cancer cells (Goswami et al.,2005).

PBXIP1 was shown to be up-regulated in colorectal cancer, oral squamouscell carcinoma, high-grade glioma, ependymoma and liver cancer (Xu etal., 2013b; van Vuurden et al., 2014; Okada et al., 2015; Feng et al.,2015b). PBXIP1 is associated with breast cancer and hepatocellularcarcinoma (Okada et al., 2015; Bugide et al., 2015; Wang et al., 2008).PBXIP1 promotes cell migration and invasion in colorectal cancer (Fenget al., 2015b). PBXIP1 is associated with poor clinical outcome incolorectal cancer and overall survival in leiomyosarcoma (Silveira etal., 2013; Feng et al., 2015b).

PCBP4 was shown to be down-regulated in lung cancer (Pio et al., 2004).

PDIA3 may be used as a biomarker and in the diagnosis of tumors(Shishkin et al., 2013). PDIA3 is differentially expressed in gliomas(Deighton et al., 2010). PDIA3 is implicated in human pathologyincluding cancer and Alzheimer's disease (Coe and Michalak, 2010). PDIA3is an auxiliary factor of TAP which loads viral and self-peptides on MHCclass I (Coe and Michalak, 2010; Abele and Tampe, 2011).

PHB activates the Raf/MEK/ERK pathway which is involved in cell growthand malignant transformation (Rajalingam and Rudel, 2005). PHB is apotential biomarker in nasopharyngeal carcinoma that predicts thetreatment response to radiotherapy (Chen et al., 2015e). PHB wasidentified in the proteomic analysis of drug-resistant cancer cells,drug action, and disease state tissues (Guo et al., 2013). PHB isover-expressed in many cancer entities (Zhou and Qin, 2013). The coreprotein of hepatitis C virus, which is a major risk factor forhepatocellular carcinoma, induces over-production of oxidative stress byimpairing prohibitin (Theiss and Sitaraman, 2011; Schrier and Falk,2011; Koike, 2014). PHB is differentially expressed in gliomas (Deightonet al., 2010).

PHF20L1 was shown to be associated with breast cancer in the cell lineZR-75-30 (Schulte et al., 2012). PHF20L1 is associated with ovariancancer (Wrzeszczynski et al., 2011).

PHKG2 is frequently methylated in papillary thyroid cancer (Kikuchi etal., 2013). PHKG2 is de-regulated in endometrial carcinomas and mayfunction as a molecular biomarker (Colas et al., 2011).

PHRF1 is associated with acute promyelocytic leukemia (Prunier et al.,2015). PHRF1 was shown to be deleted or silenced in breast cancer(Ettahar et al., 2013).

Elevated levels of PI4KA were observed in hepatocellular carcinomaversus normal liver tissue. In addition, the PI4KA gene was detected inpancreatic cancer cell line (Ishikawa et al., 2003; Ilboudo et al.,2014). Patients suffering from hepatocellular carcinoma with higherPI4KA mRNA concentrations had a higher risk of tumor recurrence as wellas shorter disease-specific survival (Ilboudo et al., 2014). Recently,PI4KA has been identified to be involved in cell proliferation andresistance to cisplatin treatment in a medulloblastoma cell line. Othershave revealed that PI4KA plays a crucial role in invasion and metastasisin pancreatic cancer (Ishikawa et al., 2003; Guerreiro et al., 2011).

Researchers have demonstrated the use of loss of GPI-anchored proteinexpression resulting from PIGA mutation as a new technique for findingmutator (Mut) phenotypes in cancer (Chen et al., 2001). Recent work hasrevealed that PIGA causes apoptosis in rat C6 glioma cells. In addition,cytosolic accumulation of cytochrome c, caspase-3 activation and DNAfragmentation were observed in PIGA-treated cells. Others have reportedthat leukemic cells with PIGA mutations were less susceptible than theircontrol counterparts to be killed by natural killer cells in vitro(Nagakura et al., 2002; Chelli et al., 2005).

Single nucleotide polymorphism in the PIGK gene was detected in patientsaffected by colorectal cancer. Another report observed down-regulationof PIGK mRNA level in bladder carcinoma, hepatocellular carcinoma andcolon carcinoma (Nagpal et al., 2008; Dasgupta et al., 2012).

PJA1 was shown to be up-regulated in gastric cancer (Mishra et al.,2005a).

Over-expression of PJA2 was found in lysates from papillary thyroidcancer and glioblastoma samples compared to anaplastic thyroid cancers(Cantara et al., 2012; Lignitto et al., 2013). In addition, PJA2-FERtyrosine kinase mRNA chimeras were found to be associated with poorpostoperative prognosis in non-small cell lung cancer (Kawakami et al.,2013). Recent work has demonstrated that PJA2 is a key element incontrolling cAMP dependent PKA activity and pro-survival signaling(Hedrick et al., 2013).

PKHD1L1 was shown to be expressed as a fusion transcript in T-cell largegranular lymphocyte leukemia (Izykowska et al., 2014).

In gastric cancer, elevated levels of PLA2G6 were correlated to tumorsize, tumor differentiation, TNM stage and it was an independentpredictor of survival for patients with gastric cancer (Wang et al.,2013h). Over-expression of PLA2G6 was detected in a variety of humancancers, including cholangiocarcinomas, gastric cancer, colorectalcancer, lung cancer, pancreatic cancer, bladder cancer and Barrett'sadenocarcinoma (Wu et al., 2002;

Lagorce-Pages et al., 2004; Cai et al., 2013a; Wang et al., 2013h).Bromoenol lactone, an inhibitor of PLA2G6 caused an increase inapoptosis in ovarian cancer cells as well as inducing cell cycle arrestin S- and G2/M-phases (Song et al., 2007).

Several publications have shown up-regulation of PLAUR in various tumorssuch as urothelial neoplasia of the bladder, colorectal cancer andbreast cancer (Bianchi et al., 1994; Illemann et al., 2014; Dohn et al.,2015). Over-expression of PLAUR was correlated with overall survival ofcolorectal and gastric cancer patients (Yang et al., 2000; Seetoo etal., 2003; Alpizar-Alpizar et al., 2012).

PLCH1 is associated with squamous cell carcinoma of the lungs (Zhang etal., 2013d).

PLEKHA8 was shown to be associated with colorectal cancer (Eldai et al.,2013). PLEKHA8 was shown to be associated with responsiveness to5-fluorouracil in primary breast cancer culture cells (Tsao et al.,2010).

Recent work identified somatic missense mutations of PLXNC1 and copynumber loss in pancreatic ductal adenocarcinomas and melanoma. Anothergroup showed a significant loss of PLXNC1 in metastatic melanomacompared with primary melanoma. Others have reported down-regulation ofPLXNC1 in acute myeloid leukemia (Stirewalt et al., 2008; Lazova et al.,2009; Balakrishnan et al., 2009). It appears that PLXNC1 significantlyinhibits migration and proliferation in melanoma (Chen et al., 2013c).

POLN was shown to be borderline significant in lung cancer in agene-based association analysis (Kazma et al., 2012). POLN was shown tobe associated with increased melanoma risk in melanoma families with andwithout CDKN2A mutations (Liang et al., 2012b). POLN was shown to beinvolved in DNA repair and is associated with homologous recombinationand cross-link repair (Moldovan et al., 2010). POLN was shown to bedisrupted by translocation breakpoints in neuroblastoma and thereforemight play a role in neuroblastoma development (Schleiermacher et al.,2005).

RNA polymerase I (Pol I) activity is commonly deregulated in humancancers. POLR1A functions as the Pol I large catalytic subunit proteinand may therefore represent a therapeutic target in cancer (Colis etal., 2014). Furthermore, drug induced POLR1A destruction was shown to beassociated with cancer cell killing across NC160 cancer cell lines(Peltonen et al., 2014). Interference of POLR1A was shown to inhibitrRNA synthesis and to hinder cell cycle progression in cells withinactivated p53. Thus, POLR1A may be a novel selective target to hinderproliferation of p53-deficient cancer cells (Donati et al., 2011).

POLR1B was shown to be regulated by the proto-oncogene c-Myc (Poortingaet al., 2011). POLR1B was shown to be associated with the pathogenesisof therapy-related acute myeloid leukemia (Cahan and Graubert, 2010).

A recent study has identified POM121 as a PAX5 fusion protein inleukemia and childhood acute lymphoblastic leukemia (Nebral et al.,2009; Fortschegger et al., 2014).

Low levels of PPIP5K1 were found in the MCF7DAP3kd and MDA-MB-231DAP1 kdbreast cancer cell lines (Wazir et al., 2015a; Wazir et al., 2015b).High levels of PPIP5K1 have been shown to promote the induction of thepro-apoptotic gene TRAIL, whereas anti-apoptotic genes like BCL2, BIRC3and PRKCE were suppressed. Moreover, PPIP5K1 is able to induce caspaseactivation. A recent work has revealed that PPIP5K1 induces cancer cellmigration, invasion and tumor metastasis via LKB1 inactivation (Rao etal., 2015; Kumar et al., 2015).

Mutations in the PPP2R1A gene have been attributed to various cancerssuch as breast cancer, prostate cancer and uterine serous carcinomas.Others observed that mutations in PPP2R1A were infrequent in ovariancarcinoma, endometrioid cancer and absent in clear cell andcarcinosarcoma subtypes (Calin et al., 2000; Shih et al., 2011; Cheng etal., 2011; Nagendra et al., 2012; Rahman et al., 2013). Researchers havedemonstrated that the

PRAME was shown to be up-regulated in multiple myeloma, clear cell renalcell carcinoma, breast cancer, acute myeloid leukemia, melanoma, chronicmyeloid leukemia, head and neck squamous cell carcinoma and osteosarcomacell lines (Dannenmann et al., 2013; Yao et al., 2014a; Zou et al.,2012; Szczepanski and Whiteside, 2013; Zhang et al., 2013b; Beard etal., 2013; Abdelmalak et al., 2014; Qin et al., 2014). PRAME isassociated with myxoid and round-cell liposarcoma (Hemminger et al.,2014). PRAME is associated with shorter progression-free survival andchemotherapeutic response in diffuse large B-cell lymphoma treated withR-CHOP, markers of poor prognosis in head and neck squamous cellcarcinoma, poor response to chemotherapy in urothelial carcinoma andpoor prognosis and lung metastasis in osteosarcoma (Tan et al., 2012;Dyrskjot et al., 2012; Szczepanski et al., 2013; Mitsuhashi et al.,2014). PRAME is associated with lower relapse, lower mortality andoverall survival in acute lymphoblastic leukemia (Abdelmalak et al.,2014). PRAME may be a prognostic marker for diffuse large B-celllymphoma treated with R-CHOP therapy (Mitsuhashi et al., 2014).

Several publications have shown that translocation found in papillaryrenal cell carcinoma leads to the fusion of a PRCC gene to the TFE3transcription factor (Sidhar et al., 1996; Weterman et al., 1996;Weterman et al., 2001).

Some researchers have observed a significant increase in PRKAR1Aexpression in undifferentiated thyroid carcinomas compared to normalthyroid tissue and differentiated thyroid tumors. On the contrary,down-regulation of PRKAR1A expression was reported in a subset ofodontogenic tumors. Another group revealed that PRKAR1A could beinvolved in the pathogenesis of odontogenic myxomas as well as insporadic adrenocortical adenomas (Bertherat et al., 2003; Perdigao etal., 2005; Ferrero et al., 2015; Sousa et al., 2015).

PRKDC is a frequently mutated gene in endometriosis-associated ovariancancer and breast cancer (Er et al., 2016; Wheler et al., 2015). PRKDCis up-regulated in cancerous tissues compared with normal tissues incolorectal carcinoma. Patients with high PRKDC expression show pooreroverall survival (Sun et al., 2016).

Over-expression of PRKX was detected in keratocystic odontogenic tumorof the jaw bones (Kong et al., 2015). It was reported thatdown-regulation of PRKX sensitized kidney carcinoma and melanoma-celllines against Sunitinib. Similarly, decreased levels of PRKX weredetected in the three FOLR1 siRNA-treated taxol-resistant nasopharyngealcarcinoma cells (Bender and Ullrich, 2012; Song et al., 2015b).

Studies have detected expression of PRKY in prostate cancer tissues,whereas in gonadoblastoma PRKY expression was undetectable (Dasari etal., 2001; Lau and Zhang, 2000; Su et al., 2006).

PRPF8 is associated with poor prognosis in acute myeloid leukemia anddrug resistance in Mcl1-dependent neuroblastoma (Laetsch et al., 2014;Kurtovic-Kozaric et al., 2015).

PRRC1 was shown to be fused with MLL in secondary acute lymphoblasticleukemia (Douet-Guilbert et al., 2014).

It has been reported that PSAP is amplified and over-expressed in anumber of androgen independent human prostate cancer cell lines, breastcancer cell lines and esophageal squamous cell carcinoma (Koochekpour etal., 2005b; Pawar et al., 2011; Wu et al., 2012f). Furthermore, highmRNA levels of PSAP were significantly linked with shorterprogression-free survival in patients suffering from breast cancer withrecurrent disease treated with first-line tamoxifen therapy (Meijer etal., 2009). Recent studies showed that PSAP induces cell proliferation,migration and invasion in prostate cancer cell lines (Lee et al., 2004;Koochekpour et al., 2005a).

Single nucleotide polymorphisms in the PSMA4 gene have been associatedwith the risk of lung cancer in Chinese Han population. Others reportedthat single nucleotide polymorphisms in the PSMA4 gene are no majorcontributors to non-small cell lung cancer susceptibility. In addition,over-expression of PSMA4 was observed in lung tumors compared to normallung tissues (Liu et al., 2008a; Liu et al., 2009b; Yongjun Zhang etal., 2013; Wang et al., 2015e).

Up-regulation of PSMC2 has been reported in tumors of transgenic mice aswell as in human hepatocellular carcinoma (Cui et al., 2006). It hasbeen postulated that PSMC2 could play an important role in the apoptosisand partial differentiation of acute promyelocytic leukemia cell line(Wang et al., 2003).

PSMC3 was identified as human gastric carcinoma-associated antigen. Inaddition, PSMC3 was able to react with sera from patients suffering fromhepatocellular carcinoma (Zeng et al., 2007; Uemura et al., 2003).

PSMC4 is significantly and coherently up-regulated in prostate carcinomacells compared with the corresponding adjacent normal prostate tissue(Hellwinkel et al., 2011).

Increased PSMD4 levels were detected in colon cancer, myeloma andhepatocellular carcinoma (Arlt et al., 2009; Midorikawa et al., 2002;Shaughnessy, Jr. et al., 2011).

Increased expression of PSMD8 in the peripheral lung may be potentiallyinformative as to what critical cell populations are involved in thedevelopment of invasive cancers (Zhou et al., 1996).

PTPLAD2 was shown to be down-regulated in esophageal squamous cellcarcinoma, which is correlated with poor prognosis (Zhu et al., 2014b).PTPLAD2 was shown to interact with STAT3 and to inhibit tumorproliferation upon up-regulation. Thus, PTPLAD2 is a potential tumorsuppressor and prognostic indicator as well as a possible target foresophageal squamous cell carcinoma treatment (Zhu et al., 2014b).PTPLAD2 was described as a novel candidate tumor suppressor geneencompassed within homozygously deleted loci in glioblastoma (Nord etal., 2009).

Down-regulation of PTPN2 protein levels were observed in a subset ofhuman breast cancer cell lines. In addition, PTPN2 was deleted in allhuman T-cell acute lymphoblastic leukemias. Furthermore, a bi-allelicinactivation of the PTPN2 gene was identified in the Hodgkin's lymphomacell line SUP-HD1 (Kleppe et al., 2010; Kleppe et al., 2011a; Kleppe etal., 2011 b; Shields et al., 2013). Recent work has revealed that PTPN2gene loss and lower mRNA levels were correlated with poor prognosis inbreast cancer (Karlsson et al., 2015). It seems that PTPN2 acts asclassical tumor suppressor via inhibition of JAK/STAT signaling pathways(Kleppe et al., 2011 b).

Elevated levels of PTPRU expression were found in gastric cancer tissuesas well as in glioma. Others have reported PTPRU to act as a tumorsuppressor in colon cancer (Yan et al., 2006; Zhu et al., 2014c; Liu etal., 2014i). Furthermore, knockdown of PTPRU repressed growth andmotility in gastric cancer, whereas in glioma it suppressedproliferation, survival, invasion, migration and adhesion. In breastcancer, PTPRU prevents tumor growth and the formation of metastases (Zhuet al., 2014c; Liu et al., 2014i; Liu et al., 2015f).

PWP1 was shown to be up-regulated in pancreatic cancer (Honore et al.,2002).

Over-expression of PYGL was observed in a multidrug-resistant cancercell line. In addition, polymorphisms in the PYGL gene were correlatedwith higher risk of relapse in childhood acute lymphoblastic leukemia(Heim and Lage, 2005; Yang et al., 2012c).

RAD54L2 is associated with shorter overall survival in gastrointestinalstromal tumors (Schoppmann et al., 2013).

RALGAPB depletion was shown to cause chromosome misalignment anddecrease of mitotic cyclin B1, whereas over-expression interfered withcell division. Deregulation of RALGAPB might cause genomic instability,leading to carcinogenesis (Personnic et al., 2014). Suppression of theRal GTPase activating protein was shown to cause mTORC1-dependentpancreatic tumor cell invasion, indicating a crosstalk between the Raland mTOR signaling networks. MTOR signaling is associated with cancer(Martin et al., 2014).

Several publications have observed diminished RARRES3 expression inbasal cell carcinomas and in advanced squamous cell carcinomas (DiSepioet al., 1998; Duvic et al., 2000; Duvic et al., 2003). In addition,RARRES3 was shown to inhibit RAS signaling pathways in cervical cancercells (Tsai et al., 2006). In skin cancer, RARRES3 has been shown toinduce pericentrosomal organelle accumulation, which in turn resulted inreduced cyclin D1, cyclin E and cyclin A levels and increased p21 level.Moreover, in testicular cancer cells RARRES3 significantly inhibitedcell migration and invasion (Scharadin et al., 2011; Wu et al., 2012b).

RASAL2 is a RAS-GTPase-activating protein with tumor suppressorfunctions in estrogen receptor-positive breast cancer, ovarian cancerand lung cancer (Huang et al., 2014d; Li and Li, 2014). In contrast,RASAL2 is oncogenic in triple-negative breast cancer and drivesmesenchymal invasion and metastasis (Feng et al., 2014b).

RASGEF1B was described as a promoter of Ras activation which isregulated by the cell cycle-associated transcription factor E2F1(Korotayev et al., 2008).

RBM47 is associated with breast cancer progression and metastasis(Vanharanta et al., 2014).

Recent work revealed down-regulation of RCC1 in poorly differentiatedgastric cell lines and gastric carcinoma tissues. Others have reportedelevated levels of RCC1 in response to PTEN expression in a PTEN-nullT-cell leukemia line (Huang et al., 2005b; Lin et al., 2015c). Ingastric cancer, loss of RCC1 expression was associated with tumordifferentiation and depth of invasion (Lin et al., 2015c).

REC8 encodes REC8 meiotic recombination protein a member of the kleisinfamily of structural maintenance of chromosome protein partners (RefSeq,2002). A recent study has revealed that the REC8 gene is heterogeneouslyexpressed in patients with cutaneous T-cell lymphoma as well as inpatient-derived cell lines. Others have shown that REC8 washypermethylated in melanoma. In addition, REC8 was constitutivelyexpressed in endopolyploid tumor cells (Litvinov et al., 2014a; Furutaet al., 2006; Erenpreisa et al., 2009). Hyper-methylation of REC8 hasbeen correlated with poor clinicopathological outcomes of patientsaffected by thyroid cancer, including advanced tumor, disease stages andpatient mortality (Liu et al., 2015a).

Genomic rearrangement or over-expression of RFX3 has been detected inpapillary tumors of the pineal region and primary testicular diffuselarge B cell lymphoma. Others have reported low levels of RFX3expression in gastric cancer cells (Twa et al., 2015; Fevre-Montange etal., 2006; Seidl et al., 2010).

Mutations in the RFX5 gene have been found in microsatellite instabilitycolorectal cancer lesions. These findings suggest that mutations of theRFX5 gene represent a new mechanism of loss of HLA class II antigenexpression in tumor cells. Recent work has shown that RFX5 is related togastrointestinal cancer (Satoh et al., 2004; Michel et al., 2010;Surmann et al., 2015).

RHPN2 was shown to be associated with colorectal cancer (He et al.,2015). A RHPN2 polymorphism may be a prognostic biomarker for patientswith surgically resected colorectal cancer (He et al., 2015). RHPN2 wasshown to be associated with survival outcome, worse prognosis fordisease-free survival and overall survival in colorectal cancer anddecreased survival of patients with glioblastoma (Danussi et al., 2013;Kang et al., 2015a). RHPN2 was shown to play a role in the formation ofhuman pituitary nonfunctional adenoma (Zhan and Desiderio, 2006).

RINT1 is described as an oncogene in glioblastoma multiforme and as amoderately penetrant cancer susceptibility gene seen in breast cancer aswell as in Lynch syndrome-related cancers (Ngeow and Eng, 2014; Quayleet al., 2012).

RIPK3 was shown to be down-regulated in colorectal cancer, breast cancerand serous ovarian cancer (McCabe et al., 2014; Koo et al., 2015a; Fenget al., 2015a). RIPK3 expression is associated with the clinical outcomeof PolylC-based immunotherapeutic approaches in cervical cancer andbetter survival in the osteosarcoma cell line U2OS after 5-aminolevulicacid-mediated photodynamic therapy (Coupienne et al., 2011; Schmidt etal., 2015). RIPK3 is associated with non-Hodgkin lymphoma and lungcancer (Yang et al., 2005; Fukasawa et al., 2006; Cerhan et al., 2007).RIPK3 is an independent prognostic factor for overall survival anddisease-free survival in colorectal cancer (Feng et al., 2015a). RIPK3is a potential marker for predicting cisplatin sensitivity inapoptosis-resistant and advanced esophageal cancer (Xu et al., 2014b).

RIPK4 was shown to be down-regulated in squamous cell carcinoma of theskin (Poligone et al., 2015). RIPK4 is associated with migration andinvasion in the tongue squamous cell carcinoma cell line Tca-8113,survival of diffuse large B-cell lymphoma and overall as well asdisease-free survival, progression and poor prognosis in cervicalsquamous cell carcinoma (Wang et al., 2014h; Liu et al., 2015b; Kim etal., 2008e). RIPK4 is associated with familial pancreatic cancer (Lucitoet al., 2007). RIPK4 may be a potential diagnostic and independentprognostic biomarker for cervical squamous cell carcinoma and abiomarker for tongue cancer prognosis and treatment (Wang et al., 2014h;Liu et al., 2015b).

Point mutations of the RING domain of RNF167 have been identified inhuman tumor samples, which abrogate ubiquitin ligase activity andfunction (van Dijk et al., 2014). RNF167 functions in concert with UbcH6as an ubiquitin ligase for the putative tumor suppressor TSSC5, a genefound to be mutated in certain tumors. Together with UbcH6, RNF167 maydefine a novel ubiquitin-proteasome pathway that targets TSSC5 (Yamadaand Gorbsky, 2006).

RNF20 was shown to be down-regulated in testicular seminoma andmetastatic prostate cancer (Jaaskelainen et al., 2012; Chernikova etal., 2012).

RNF213 is associated with chronic myeloid leukemia (Zhou et al., 2013b).RNF213 is associated with poor prognosis in anaplastic lymphoma kinasepositive anaplastic large cell lymphoma (Moritake et al., 2011).

RNF31 was shown to be up-regulated in breast cancer and in lungmetastasis of the osteosarcoma LM8 cell line (Tomonaga et al., 2012; Zhuet al., 2015). RNF31 is associated with the activated B cell-likesubtype of diffuse large B-cell lymphoma (Yang et al., 2014f; Grumatiand Dikic, 2014). RNF31 is associated with cisplatin-resistance inovarian cancer (Mackay et al., 2014).

Down-regulation of RNF40 has been reported in testicular germ cellcancer seminoma compared to normal testis. Others have also observed lowlevels of RNF40 in colorectal cancer (Chernikova et al., 2012; Tarcic etal., 2016). Moreover, loss of RNF40 strongly retarded the growth ofprostate cancer cells (Jaaskelainen et al., 2012).

Recently, a mutation in the RQCD1 gene was identified in melanoma. Inaddition, over-expression of RQCD1 was found in breast cancer specimensas well as breast cancer cell lines (Ajiro et al., 2009; Wong et al.,2015). In breast cancer cell lines, RQCD1 protein was shown to interactwith GIGYF1 and GIGYF2 proteins, which are involved in regulation of Aktactivation. Furthermore, knockdown of RQCD1 resulted in a reduction inthe Akt phosphorylation level that was induced by epidermal growthfactor stimulation (Ajiro et al., 2009; Ajiro et al., 2010).

Recent work has demonstrated that over-expression of RTN2 inducesanti-estrogen resistance in human breast cancer cell lines (Near et al.,2007; Makkinje et al., 2009).

Over-expression of RTN3 was detected in the saliva of patients sufferingfrom oral squamous cell cancer. Similarly, elevated levels of RTN3 weredetected in the sera of epithelial ovarian carcinoma patients in allstages, but in particular it was highest in stage III. Others haveobserved high levels RTN3 in leukemia and urogenital cancer (Mitchell etal., 1988; Dunzendorfer et al., 1980; Chen et al., 2009c; Jessie et al.,2013). Furthermore, it was shown that circulating RTN3 was significantlyassociated with the stage of tumor and survival of epithelial ovariancarcinoma patients (Zhao et al., 2007).

SAMD9 was shown to be down-regulated in breast cancer, colon cancer,non-small cell lung cancer and fibromatosis (Ma et al., 2014; Li et al.,2007). SAMD9 is associated with invasion, migration and proliferation inthe non-small cell lung cancer cell line H1299, lymphatic invasion andmetastasis in esophageal squamous cell carcinoma and myeloid leukemias(Nagamachi et al., 2013; Tang et al., 2014b; Ma et al., 2014).

SAMSN1 was shown to be up-regulated in glioblastoma multiforme (Yan etal., 2013c). SAMSN1 was shown to be down-regulated in hepatocellularcarcinoma, multiple myeloma and in the large cell lung carcinoma cellline Calu-6 (Noll et al., 2014; Sueoka et al., 2015; Yamada et al.,2008). SAMSN1 is associated with ulcerative colitis-associated cancerand acute myeloid leukemias (Watanabe et al., 2011; Claudio et al.,2001). SAMSN1 is associated with shorter overall and recurrence-freesurvival in hepatocellular carcinoma and poor overall survival ofglioblastoma multiforme (Yan et al., 2013c; Sueoka et al., 2015). SAMSN1is an independent prognostic factor of hepatocellular carcinomaprogression and a potential prognostic marker of multiple myeloma (Ni etal., 2012; Sueoka et al., 2015).

SCARA3 was shown to be up-regulated in ovarian/primary peritonealcarcinoma (Bock et al., 2012). SCARA3 is a predictor of multiple myelomaprogression and therapeutic response (Brown et al., 2013).

Methylation of SCNN1A was detected in breast cancer cell lines as wellas in neuroblastoma. A recent study suggested that SCNN1A could beimplicated in the aetiology of testicular germ cell tumors, sinceretinoic acid suppresses the tumorigenicity of embryonal carcinoma cells(Giuliano et al., 2005; Roll et al., 2008; Caren et al., 2011).Researchers have used a cox proportional hazards model and showed thatSCNN1A could predict patients' prognosis in adenocarcinoma (Endoh etal., 2004).

SEC61A1 is associated with prostate cancer (Bull et al., 2001).

SEC61G was shown to be up-regulated in gastric cancer (Tsukamoto et al.,2008). SEC61G is associated with gliomas (Neidert et al., 2013).

SESN3 was described as a unique cellular inhibitor of mTOR complex 1(Vakana et al., 2013). SESN3 was described to be induced through thetumor suppressor FOXO3 in the context of reactive oxygen speciesdetoxification (Hagenbuchner and Ausserlechner, 2013). SESN3 repressionwas shown to be induced through oncogenic Ras in the context ofregulation of reactive oxygen species upon cell proliferation (Zamkovaet al., 2013). SESN3 was shown to be regulated by the tumor suppressorp53 upon nerve growth factor-mediated differentiation of the PC12 cellline (Brynczka et al., 2007). SESN3 5′ CpG island methylation was shownto be a novel endometrial cancer-specific marker (Zighelboim et al.,2007).

Researchers have identified SETDB1 as a novel oncogene in a zebrafishmelanoma model as well as in human lung cancers. Furthermore,over-expression of SETDB1 has been found in non-small cell lung cancer,prostate cancer and glioma (Ceol et al., 2011; Rodriguez-Paredes et al.,2014; Spyropoulou et al., 2014; Sun et al., 2014d; Sun et al., 2015f).It appears that SETDB1 is able to positively stimulate the activity ofthe WNT-beta-catenin pathway (Sun et al., 2015f). In addition, knockdownof SETDB1 by siRNA inhibited prostate cancer cell growth, invasion,migration, reduced colony formation and induced cell cycle arrest (Sunet al., 2014d).

SGPP2 was shown to be down-regulated in sphingosine-1-phosphate enrichedglioblastomas (Abuhusain et al., 2013). SGPP2 was shown to be a NF-kBdependent gene which thus might be a potential novel player inpro-inflammatory signaling (Mechtcheriakova et al., 2007).

SH3GLB2 was shown to be up-regulated in prostate cancer metastasis(Fasso et al., 2008).

SHISA5 is associated with squamous cell carcinoma of the head and neck(Ghosh et al., 2008).

Increased SIGLEC1 expression has been observed in splenic marginal celllymphoma as well as in AIDS-related Kaposi's sarcoma. Others have foundmutations in the SIGLEC1 gene to be linked to the development ofpancreatic ductal adenocarcinoma (Zhou et al., 2012a; Cornelissen etal., 2003; Marmey et al., 2006). Elevated levels of SIGLEC1 expressioncorrelated with a better prognosis in patients suffering from colorectalcarcinoma and malignant melanoma (Ohnishi et al., 2013; Saito et al.,2015).

SIN3A was shown to be associated with invasion in the lungadenocarcinoma cell line A549 (Das et al., 2013b). SIN3A is associatedwith breast cancer (Ellison-Zelski and Alarid, 2010). SIN3A was shown tobe down-regulated in non-small cell lung cancer (Suzuki et al., 2008).

Over-expression of SKIL has been observed in human breast cancer celllines, lung adenocarcinoma cell lines, melanoma and osteosarcoma. Othersreported that SKIL was amplified in primary esophageal squamous cellcarcinomas (Imoto et al., 2001; Zhang et al., 2003; Zhu et al., 2007).In breast cancer, reduced expression of SKIL was associated with longerdistant disease-free survival in estrogen receptor-positive patients(Zhang et al., 2003).

A study has revealed that the highest SLC15A2 mRNA levels were found onprostate cancer cell line LNCaP compared to PC-3 and DU145 cells. Othersreported that genomic variants in the SLC15A2 gene could be associatedwith sorafenib response in patients suffering from hepatocellularcarcinoma (Tai et al., 2013; Lee et al., 2015).

SLC15A3 is associated with colorectal cancer (Zhou et al., 2013a).SLC15A3 was shown to be associated with prostate cancer in the prostatecancer cell lines LNCaP, DU-145, PC-3 and MDA2b (Ibragimova et al.,2010).

Down-regulation of SLC16A2 was reported in medullary thyroid carcinomascompared to non-tumor thyroid tissue (Hudson et al., 2013).

A report has shown that the expression of SLC25A14 was significantly andnegatively associated with postmenopausal human breast tumors with a lowERalpha/ERbeta ratio. Others have observed elevated levels of SLC25A14in breast cancer cell lines with low ERalpha/ERbeta ratio. In addition,high levels of SLC25A14 were found in colonic cancer cells, which werecorrelated with mitochondrial dysfunction (Santandreu et al., 2009;Nadal-Serrano et al., 2012; Sastre-Serra et al., 2013).

SLC28A3 was shown to be down-regulated in pancreatic ductaladenocarcinoma (Mohelnikova-Duchonova et al., 2013a). SLC28A3 isassociated with clinical outcome in metastatic breast cancer treatedwith paclitaxel and gemcitabine chemotherapy, overall survival ingemcitabine treated non-small cell lung cancer and overall survival ingemcitabine-based chemoradiation treated pancreatic adenocarcinoma (Liet al., 2012c; Lee et al., 2014b; Marechal et al., 2009). SLC28A3 isassociated with fludarabine resistance in chronic lymphocytic leukemiaand drug resistance in T-cell leukemia (Karim et al., 2011;Fernandez-Calotti et al., 2012).

SLC29A3 is associated with overall survival in non-small cell lungcancer patients treated with gemcitabine-based chemotherapy and overallsurvival in pancreatic cancer patients treated with nucleoside analogs(Mohelnikova-Duchonova et al., 2013a; Chen et al., 2014f). SLC29A3 is apotential prognostic biomarker for patients with advanced non-small celllung cancer who receive gemcitabine (Chen et al., 2014f).

The expression of SLC34A2 was significantly different between surgicalsamples of non-small cell lung cancer and normal tissues. Furthermore,low levels of SLC34A2 expression were found in lung adenocarcinoma celllines. Others have demonstrated that SLC34A2 could be the target ofMX35, an antibody developed to treat ovarian cancer (Yin et al., 2008;Yang et al., 2014c; Wang et al., 2015k). Moreover, up-regulation ofSLC34A2 in lung adenocarcinoma cell lines was able to significantlyinhibit cell viability and invasion in vitro (Wang et al., 2015k). Onthe other hand, decreased SLC34A2 expression sensitized breast cancerstem cells to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling (Ge et al.,2015).

SLC35B3 is associated with colorectal carcinoma (Kamiyama et al., 2011).SLC35B3 was shown to be associated with chemotherapy resistance inovarian cancer (Cheng et al., 2010).

SLC35E1 was shown to be associated with rectal carcinoma response toneoadjuvant radiochemotherapy (Rimkus et al., 2008).

Down-regulation of SLC35E2 has been reported in neuroblastoma (Thorellet al., 2009).

The SLC35E2B transcripts showed significantly lower expression inunfavorable neuroblastoma tumors (Thorell et al., 2009).

Over-expression of SLC4A2 has been observed in colon cancer andhepatocellular carcinoma. On the other hand, SLC4A2 expression wasdown-regulated in gastric cancer (Wu et al., 2006; Yang et al., 2008b;Song et al., 2012). In colon cancer, elevated levels of SLC4A2 werecorrelated with poor prognosis (Song et al., 2012). In addition,inhibition of SLC4A2 expression reduced cell viability, arrested cellcycle at sub-G1 phase, and induced cell apoptosis in poorlydifferentiated hepatocellular carcinoma cells (Hwang et al., 2009).

SLC7A8 is associated with leiomyoma (Xia et al., 2010; Luo et al.,2009). SLC7A8 was shown to be associated with drug resistance in ovariancancer cell line W1 variants (Januchowski et al., 2013). SLC7A8 wasshown to be up-regulated in the estrogen receptor alpha positive breastcancer cell line T-47D (Thakkar et al., 2010).

Several publications have reported increased expression of SMARCC1 mRNAand protein in prostate cancer, colorectal cancer and cervicalintraepithelial neoplasia. In contrast, SMARCC1 protein expression wasnot detected in ovarian cancer cell lines (Shadeo et al., 2008; Heebollet al., 2008; Andersen et al., 2009; DelBove et al., 2011). Furthermore,over-expression of SMARCC1 was associated with poor prognosis andrecurrence in colorectal cancer (Andersen et al., 2009). Researchershave shown that methylation of SMARCC1 at arginine residue R1064 affectsthe colony-formation capacity of MCF7 breast cancer cells. Moreover, itseems that this modification is entirely dependent on CARM1 (Wang etal., 2014e).

SMCHD1 is associated with hematopoietic cancers (Leong et al., 2013).

SMG1 was shown to be up-regulated in pancreatic cancer (Wang et al.,2015d). SMG1 was shown to be down-regulated in hepatocellular carcinoma(Han et al., 2014). SMG1 was shown to be associated with gemcitabine andcisplatin chemosensitivity in pancreatic cancer cell lines and in thelung cancer cell line H1299 and sorafenib resistance in hepatocellularcarcinoma cell lines (Xia et al., 2011; Nam et al., 2014; Wang et al.,2015d). SMG1 is associated with acute myeloid leukemia (Du et al.,2014a). SMG1 is associated with poor overall survival in hepatocellularcarcinoma (Han et al., 2014).

SMPD4 was shown to be associated with cellular stress response, DNAdamage and p53 activation and expression was shown to be deregulated inseveral types of primary tumors (Corcoran et al., 2008).

SND1 was shown to be up-regulated in non-small cell lung cancer, breastcancer, colon cancer, hepatocellular carcinoma, glioma and prostatecancer (Cappellari et al., 2014; Emdad et al., 2015; Yu et al., 2015a;Zagryazhskaya et al., 2015). SND1 is associated with chemoresistance innon-small cell lung cancer (Zagryazhskaya et al., 2015). SND1 isassociated with prostate cancer, primary cutaneous malignant melanomaand cutaneous malignant melanoma metastases (Sowalsky et al., 2015; Sandet al., 2012). SND1 is associated with migration and invasion inhepatocellular carcinoma (Santhekadur et al., 2014). SND1 is associatedwith shorter overall survival and poor prognosis in colon cancer (Wanget al., 2012b). SND1 is a promising prostate cancer biomarker (Kuruma etal., 2009).

SNRPE was over-expressed in hepatocellular carcinoma as well as inhigh-grade prostate cancer (Jia et al., 2011; Anchi et al., 2012; Xu etal., 2015c). Furthermore, elevated levels of SNRPE were correlated withworse prognosis in patients with lung cancer (Valles et al., 2012).siRNA-mediated depletion of SNRPE resulted in reduction of cellviability in breast, lung and melanoma cancer cell lines (Quidville etal., 2013).

Studies have detected high levels of serum SORL1 in follicular lymphoma,diffuse large B-cell lymphoma and peripheral T-cell lymphoma patientscompared to healthy controls. Another report also observed elevatedlevels of SORL1 in acute leukemia patients, whereas patients with acutemyeloid leukemia and acute lymphoblastic leukemia in remission exhibitedsignificantly decreased SORL1 levels. Additionally, down-regulation ofSORL1 was also seen in high-grade astrocytomas (MacDonald et al., 2007;Sakai et al., 2012; Bujo, 2012; Fujimura et al., 2014).

Over-expression of SOS1 was found in Egyptian patients suffering frombladder cancer as well as prostate cancer epithelial cells. Anotherreport has identified missense SOS1 mutations in a single pancreatictumor, one lung adenocarcinoma and a T-cell acute lymphoblastic leukemiacell line (Zekri et al., 2015; Swanson et al., 2008; Timofeeva et al.,2009). In prostate cancer cells, depletion of SOS1 resulted in decreasedcell proliferation, migration and invasion (Timofeeva et al., 2009).

SOX17 was shown to be down-regulated in breast cancer, penile carcinoma,hepatocellular carcinoma, acute myeloid leukemia and esophageal squamouscell carcinoma (Kuo et al., 2014; Tang et al., 2014a; Yang et al.,2014b; Kuasne et al., 2015; Fu et al., 2015). SOX17 is associated withovarian cancer, oligodendroglioma, melanoma, papillary thyroid carcinomaand gastric cancer (Oishi et al., 2012; Li et al., 2012b; Lu et al.,2014a; Li et al., 2014b; Du et al., 2015b). SOX17 is associated withpoor disease-free survival and overall survival in breast cancer,progression and unfavorable survival of melanoma patients, shorteroverall survival in acute myeloid leukemia and overall survival ingastric cancer (Balgkouranidou et al., 2013; Tang et al., 2014a; Lu etal., 2014a; Fu et al., 2015). SOX17 is a useful prognostic biomarker forbreast cancer, melanoma, germ cell cancer and esophageal squamous cellcarcinoma (Kuo et al., 2014; van der Zwan et al., 2015; Lu et al.,2014a; Fu et al., 2015).

SP140 was shown to be up-regulated in laryngeal squamous cell carcinoma(Zhou et al., 2007). SP140 is associated with chronic lymphocyticleukemia, multiple myeloma and acute promyelocytic leukemia (Bloch etal., 1996; Lan et al., 2010; Kortum et al., 2015).

SPG11 was shown to be down-regulated in the gastric cancer cell lineHSC45-M2 in response to treatment with alpha-emitter (213)Bi conjugatedantibodies and may be a potential new target for selective eliminationof tumor cells (Seidl et al., 2010).

Elevated expression and activity of SPLTC1 was detected in malignanttissues and in endometrial cancer tissue (Carton et al., 2003; Knapp etal., 2010). Moreover, SPTLC1 could be used as a potential therapeutictarget to alleviate imatinib resistance in BCR-ABL-positive leukemiacells (Taouji et al., 2013).

SPTLC3 is associated with invasive micropapillary carcinoma of thebreast (Gruel et al., 2014).

SRGAP1 was shown to be associated with glioblastoma multiforme in thecell lines U87-IM3 and U251-IM3, familial forms of non-medullary thyroidcarcinoma, papillary thyroid carcinoma and epithelial ovarian cancer (Heet al., 2013; Chen et al., 2014c; Pereira et al., 2015; Koo et al.,2015b).

STARD10 was shown to be up-regulated in breast cancer (Olayioye et al.,2005). STARD10 is associated with poor prognosis in breast cancer(Murphy et al., 2010).

Researchers have identified single nucleotide polymorphisms as well asmutations in the STAT6 gene to be involved in the development ofcervical cancer and follicular lymphoma. Moreover, over-expression ofSTAT6 was noted in solitary fibrous tumor, prostate and colon cancer (Niet al., 2002; Li et al., 2008a; Yoshida et al., 2014; Zhang et al.,2014g; Yildiz et al., 2015). Others have reported that STAT6 knockdowninduces the inhibition of cell proliferation, G1/S phase arrest andapoptosis in HT-29 colon cancer cells. On the contrary,un-phosphorylated STAT6 increases the expression of COX-2, therebyprotecting non-small cell lung cancer against apoptosis (Zhang et al.,2006; Cui et al., 2007).

De-regulated expression of STK17A is associated with different cancertypes. Decreased expression in cervical and colorectal cancer is relatedto the pro-apoptotic character of STK17A connected with tumorprogression. STK17A in glioblastoma and head and neck cancer isover-expressed in a grade-dependent manner, maybe caused through theinfluence on other tumor relevant pathways like TGF-beta (Mao et al.,2013a; Thomas et al., 2013; Park et al., 2015; Bandres et al., 2004).STK17A is a direct target of the tumor suppressor gene p53 and amodulator of reactive oxygen species (ROS) (Kerley-Hamilton et al.,2005; Mao et al., 2011).

Hypermethylation of STK3 was found in soft tissue sarcoma, whereas insquamous cell carcinomas of head and neck it was less frequent. Othersreported that loss of STK3 resulted in the development of hepatocellularcarcinoma (Seidel et al., 2007; Zhou et al., 2009; Steinmann et al.,2009).

STK35 was shown to regulate CDKN2A and to inhibit G1- to S-phasetransition in endothelial cells, thus, playing a role in the linkage ofthe cell cycle and migration of endothelial cells (Goyal et al., 2011).

STK38 is associated with B-cell lymphoma (Bisikirska et al., 2013).STK38 was shown to be associated with radiosensitivity in the cervicalcancer cell line HeLa (Enomoto et al., 2013). STK38 was shown to bedown-regulated in gastric cancer (Cui et al., 2005). STK38L was shown tobe down-regulated in human skin tumors (Hummerich et al., 2006). STK38Lis associated with glioma (Deng et al., 2005).

STRADA is a regulatory partner of the tumor suppressor LKB1 (Sun et al.,2015a). STRADA was shown to play a role in cell proliferation andviability of the prostate cancer cell line LNCaP and thus may be a novelprostate cancer drug target (Dahlman et al., 2012). STRADA was shown tobe involved in cell proliferation and cisplatin resistance inmedulloblastoma cell lines (Guerreiro et al., 2011). STRADA was shown tobe up-regulated in medulloblastoma (Guerreiro et al., 2011). STRADA wasshown to be a breast cancer antigen (Scanlan et al., 2001).

Over-expression of STX1A was found in breast cancer as well as in smallcell lung carcinoma. Recent work has identified STX1A as a target forthe treatment of metastatic osteosarcoma (Graff et al., 2001; Diao etal., 2014; Fernandez-Nogueira et al., 2016). Studies have revealed thatthe expression of STX1A was significantly associated with a shorteroverall survival and distant metastasis-free survival in breast cancersubtypes (Fernandez-Nogueira et al., 2016). Inhibition of STX1A reducedthe proliferation and migratory capacity of glioblastoma cells (Ulloa etal., 2015).

STYXL1 is associated with Ewing's sarcoma family tumors (Siligan et al.,2005).

SVIL is significantly down-regulated in prostate cancer tissue mainlythrough promoter methylation (Vanaja et al., 2006). SVIL regulates cellsurvival through control of p53 levels. SVIL expression is necessary forthe cross-talk between survival signaling and cell motility pathways(Fang and Luna, 2013).

Researchers have observed amplifications, copy number gains and mRNAover-expression of TAF2 in high-grade serous ovarian cancers (Ribeiro etal., 2014).

Amplifications, copy number gains, or mRNA up-regulation of TAF4B hasbeen reported in high-grade serous ovarian cancers (Ribeiro et al.,2014). In addition, TAF4B is able together with AP-1 to regulate thetarget gene integrin alpha 6 involved in epithelial-to-mesenchymaltransition, hence changing the cancer related migration properties(Kalogeropoulou et al., 2010).

TANC2 was shown to be up-regulated in breast cancer (Mahmood et al.,2014).

Single nucleotide polymorphisms as well as loss of the TAP1 gene seem tobe implicated in certain cancer types such as melanoma, cervicalcarcinoma, colorectal cancer and head and neck squamous cell carcinoma.On the other hand, up-regulation of TAP1 has been observed in lungcancer and ovarian serous carcinoma (Yang et al., 2003; Meissner et al.,2005; Vermeulen et al., 2007; Yamauchi et al., 2014; Zhang et al.,2015g; Nymoen et al., 2015). In addition, expression of TAP1 wassignificantly associated with tumor grade, clinical stage, overallsurvival and progression-free survival in patients affected by prostatecancer (Tahara et al., 2015). In lung cancer, loss of TAP1 inhibitedcell proliferation and caused cell cycle arrest in a p53-independentmanner (Zhang et al., 2015g).

Some studies did not find an association between TAP2 gene polymorphismwith renal cell carcinoma and cervical cancer. In contrast, othersobserved a correlation between the TAP2 gene polymorphism andsusceptibility to chronic lymphoid leukemia. In addition, the expressionof TAP2 was reduced in breast carcinoma, gastric cancer, small cell lungcarcinoma and head and neck squamous cell carcinoma (Restifo et al.,1993; Vitale et al., 1998; Kang et al., 2000; Hodson et al., 2003; KordiTamandani et al., 2009; Bandoh et al., 2010; Ozbas-Gerceker et al.,2013).

TCERG1 was shown to function as a transcriptional co-regulator of DACH1,a transcription factor which was shown to be associated with varioustypes of cancer (Zhou et al., 2010).

TELO2 is de-regulated in different cancer types including leukemias,breast cancer and nasopharyngeal carcinoma (He et al., 2007; Sang etal., 2015; Kawagoe et al., 2004). Over-expression of TELO2 decreasescell cycle length, hyper-sensitizes the cell to apoptosis and increasestelomere length. Inhibition of TELO2 expression arrests the cell cyclereversibly (Jiang et al., 2003). Activated TELO2 is essential for thestability of PIKK family proteins like mTOR, ATM, ATR and SMG-1. TELO2plays an important role in the regulation of translation, cell growthand DNA damage signaling (Kaizuka et al., 2010; Horejsi et al., 2010).

TET3 was shown to be down-regulated in hepatocellular carcinoma,colorectal cancer and gastric cancer (Rawluszko-Wieczorek et al., 2015;Sajadian et al., 2015; Du et al., 2015a). TET3 was shown to beup-regulated in diffuse intrinsic pontine glioma (Ahsan et al., 2014).TET3 was shown to be associated with tumor hypoxia, tumor malignancy,and poor prognosis in breast cancer (Wu et al., 2015). TET3 was shown tobe associated with TNFalpha-p38-MAPK signaling (Wu et al., 2015). TET3was described as a regulator of 5-hydroxymethylation, an epigeneticmodification associated with malignant tumors. In leiomyoma, epigeneticimbalance in the 5-hydroxymethylation content was described as a resultof TET3 up-regulation which might lead to the discovery of newtherapeutic targets in leiomyoma (Navarro et al., 2014). TET3 was shownto be recurrently mutated in colon cancer and may provide a potentialtherapeutic intervention opportunity (Seshagiri et al., 2012). TET3 wasdescribed as a potential regulator of histone modification and WNTpathways in myelodysplastic syndromes and acute myeloid leukemia(Gelsi-Boyer et al., 2009).

Over-expression of TFAP2C has been found in breast carcinomas as well asin germ cell tumors (Turner et al., 1998; Hoei-Hansen et al., 2004). Itis reported that TFAP2C induces p21 expression, arrests cell cycle andsuppresses the tumor growth of breast carcinoma cells (Li et al., 2006).

Down-regulation of TFDP2 was observed in human papillary carcinomatissues, while others reported over-expression of TFDP2 inhepatocellular carcinoma compared to normal liver tissues. In addition,TFDP2 variants have been linked to ovarian cancer (Liu et al., 2003;Lapouge et al., 2005; Cunningham et al., 2009).

TH1L might play an important role in regulation of proliferation andinvasion in human breast cancer, and could be a potential target forhuman breast cancer treatment (Zou et al., 2010).

Some researchers have reported over-expression of TIMELESS protein andmRNA in hepatocellular carcinoma as well as in colorectal cancer,cervical cancer, lung cancer and prostate cancer. On the other hand,another study reported down-regulation of TIMELESS in hepatocellularcarcinomas. In addition, single nucleotide polymorphism in the TIMELESSgene were not associated with risk of prostate cancer but correlatedwith breast cancer risk (Lin et al., 2008b; Fu et al., 2012; Mazzoccoliet al., 2011; Yoshida et al., 2013; Mao et al., 2013b; Markt et al.,2015; Elgohary et al., 2015). In lung cancer, elevated levels ofTIMELESS were associated with poor overall survival (Yoshida et al.,2013).

Over-expression and epigenetic inactivation of TLE1 have been found invarious cancers including lung tumors, synovial sarcoma, malignantmesothelioma, leukemia and lymphoma (Allen et al., 2006; Fraga et al.,2008; Matsuyama et al., 2010; Seo et al., 2011; Rekhi et al., 2012).Additionally, TLE1 suppresses apoptosis induced by doxorubicin insynovial sarcoma cells. In lung cancer cell lines TLE1 was able topotentiate epithelial-to-mesenchymal transition by suppressing the tumorsuppressor gene E-cadherin (Seo et al., 2011; Yao et al., 2014b).Furthermore, it was observed that trichostatin A significantly inhibitedlung tumorigenesis in TLE1 transgenic mice (Liu et al., 2015c).

Over-expression of TLE3 has been observed in some malignant meningiomascompared to benign and atypical meningiomas. Others have reportedelevated levels of spliced isoform of TLE3 in prostate tumors as well asin prostate tumor cell lines (Cuevas et al., 2005; Nakaya et al., 2007).Studies have revealed that TLE3 mRNA levels were predictive forprogression-free survival in breast cancer patients receiving tamoxifen.In contrast, others reported that TLE3 expression does not represent aviable biomarker for taxane benefit in breast cancer. Another reportdemonstrated that TLE3 expression predicts a favorable response totaxane containing chemotherapy regimens in ovarian carcinoma (van etal., 2009; Samimi et al., 2012; Bartlett et al., 2015).

Recent work has identified a missense mutation in the TLE4 gene in acutemyeloid leukemia. Other studies have shown over-expression of TLE4 incolorectal cancer as well as in adenomas (Greif et al., 2011; Ruebel etal., 2006; Wang et al., 2016a). In colorectal cancer, elevated levels ofTLE4 were correlated with advanced Dukes stage, lymph node metastasisand poor prognosis of colorectal cancer (Wang et al., 2016a). It seemsthat over-expression of miR-93 negatively regulates mRNA and proteinexpression of TLE4 (Yu et al., 2011).

Previous studies have found over-expression of TLN1 in several tumors,including prostate cancer, oral squamous cell carcinoma, ovarian serouscarcinoma and nasopharyngeal carcinoma (Sakamoto et al., 2010; Lai etal., 2011; Tang et al., 2013; Xu et al., 2015d). Over-expression of TLN1was associated with reduced overall survival in patients suffering fromoral squamous cell carcinoma (Lai et al., 2011). It appears that TLN1S425 phosphorylation plays a crucial role in beta1 integrin activation,cell adhesion, migration, invasion and metastasis of prostate cancercells. In addition, elevated levels of TLN1 are correlated with reducedinvasion, migration as well as decreased malignancy in hepatocellularcarcinoma cell lines (Fang et al., 2014; Jin et al., 2015).

TLR7 was shown to be up-regulated in pancreatic cancer, oral squamouscell carcinoma and hepatocellular carcinoma (Mohamed et al., 2015; Ni etal., 2015; Grimmig et al., 2015). TLR7 is associated with tumor cellproliferation and chemoresistance in pancreatic cancer (Grimmig et al.,2015). TLR7 over-expression is associated with poor clinical outcome andchemotherapy resistance in lung cancer and poor prognosis in oralsquamous cell carcinoma (Ni et al., 2015; Dajon et al., 2015). TLR7 isassociated with bladder cancer (Cheng et al., 2014).

TMEM14C is associated with breast cancer survival (Burleigh et al.,2015). TMEM14C is associated with tamoxifen resistance in the breastcancer cell line ZR-75-1 (Zarubin et al., 2005).

TMEM189-UBE2V1 isoform 2 (Uev1B) was shown to be associated withubiquitin and Hrs and over-expression of the protein abrogated theability of Hrs to colocalize with the cancer-associated protein EGFR(Duex et al., 2010).

TMPRSS13 encodes a member of the type II transmembrane serine proteasefamily, which is known to function in development, homeostasis,infection, and tumorigenesis (RefSeq, 2002). TMPRSS1 3 was shown tofunction as a hepatocyte growth factor (HGF)-converting protease,converting pro-HGF to biologically active HGF. HGF was shown to interactwith the oncogene c-Met and is associated with a variety of cancers(Hashimoto et al., 2010).

TNFAIP2 encodes TNF alpha induced protein 2 and it has been suggested tobe a retinoic acid target gene in acute promyelocytic leukemia (RefSeq,2002). TNFAIP2 rs8126 polymorphism has been significantly associatedwith susceptibility of head and neck squamous cell carcinoma, gastriccancer and esophageal squamous cell carcinoma. Moreover, the TNFAIP2mRNA and protein were found to be elevated in nasopharyngeal carcinomatumor cells compared with adjacent normal tissues. Others have observedover-expression of TNFAIP2 in glioma samples (Chen et al., 2011; Liu etal., 2011; Xu et al., 2013c; Zhang et al., 2014b; Cheng et al., 2015b).Furthermore, over-expression of TNFAIP2 was correlated with shorterdistant metastasis-free survival in nasopharyngeal carcinoma patients(Chen et al., 2011).

Up-regulation of TNXB has been observed in ovarian cancer and malignantmesothelioma, whereas in peripheral nerve sheath tumors TNXB wassignificantly down-regulated. Recent work has identified TNXB inglioblastoma multiforme cell lines (Levy et al., 2007; Yuan et al.,2009; Polisetty et al., 2011; Kramer et al., 2015). Studies have shownthat deficiency in TNXB led to tumor invasion and metastasis through theactivation of the MMP2 and MMP9 genes (Matsumoto et al., 2001).

Low levels of TOB1 have been observed in gastric, lung and breastcancers. Others have shown that mice lacking TOB1 are predisposed tospontaneous formation of tumors in various tissues (Yoshida et al.,2003; Iwanaga et al., 2003; O'Malley et al., 2009; Zhang et al., 2015k).In gastric cancer, cytoplasmic expression levels of TOB1 were correlatedwith the depth of invasion, differentiation grade andtumor-node-metastasis stage (Zhang et al., 2015k). Down-regulation ofTOB1 increased the metastasis, invasion and proliferation of gastriccancer cells (Li et al., 2015a).

Some reports have shown high staining of TOMM20 in papillary thyroidcancer compared to noncancerous thyroid tissue. Others have observedthat epithelial cancer cells exhibited high levels of the mitochondrialmembrane marker TOMM20. On the contrary, no significant difference inthe mRNA expression of the TOMM20 gene was found in prostate cancertissue (Whitaker-Menezes et al., 2011; Asmarinah et al., 2014; Curry etal., 2015). In gastric cancer, over-expression of TOMM20 was correlatedwith reduced overall survival and disease-free survival (Zhao et al.,2014c).

Over-expression of TP53I3 was found in papillary thyroid carcinoma,gemcitabine resistant non-small cell lung cancer, whereas it wasdown-regulated in esophageal squamous cell carcinoma and diffuse large Bcell lymphoma. In addition, variant genotypes of (TGYCC)n repeats in theTP53I3 promoter were correlated with risk of squamous cell carcinoma ofthe head and neck. Others have reported an association of TP53I3promoter VNTRs with generation of invasive bladder cancer (Dadkhah etal., 2013; Ito et al., 2006; Guan et al., 2013; Zhu et al., 2013a; Zhanget al., 2013a; Xu et al., 2015b). Researchers have observed that TP53I3silencing in papillary thyroid carcinoma cell lines resulted in areduction in the activity of the PI3K/AKT/PTEN pathway (Xu et al.,2015b).

The TPR-MET rearrangement has been detected in several cell linesderived from human tumors of non-hematopoietic origin as well as ingastric carcinoma. One study has detected a TPR-NTRK1 fusion incolorectal cancer, while TPR-ALK fusion has been seen in lungadenocarcinoma. In addition, loss or deletion of TPR gene has beenreported in gastric cancer (Soman et al., 1991; Soman et al., 1990;Cunningham et al., 1997; Yu et al., 2000; Choi et al., 2014; Creancieret al., 2015). Recent work has revealed that TPR depletion leads toG0/G1 phase arrest, which in turn induces a senescent-like phenotype intumor cell lines (David-Watine, 2011).

TPX2 was shown to be up-regulated in hepatocellular carcinoma,pancreatic cancer, cervical cancer, medullary thyroid cancer, coloncancer and prostate cancer (Vainio et al., 2012; Wei et al., 2013; Yanget al., 2014d; Jiang et al., 2014b; Miwa et al., 2015; Liang et al.,2015b). TPX2 is associated with poor prognosis in hepatocellularcarcinoma, poor overall survival and lower disease free survival inhigh-grade serous epithelial ovarian cancer, patient outcome and poorprognosis of esophageal squamous cell carcinoma, development andprogression of bladder carcinoma and poor 5-year survival in lungadenocarcinoma (Li et al., 2013c; Yan et al., 2013a; Hsu et al., 2014;Caceres-Gorriti et al., 2014; Liang et al., 2015b). TPX2 is associatedwith colorectal cancer, non-small cell lung cancer, head and necksquamous cell carcinoma, metastasis of ER positive breast cancer,metastasis of hepatocellular carcinoma, metastasis and disease stage ofmedullary thyroid cancer and metastasis of colon cancer (Martens-de Kempet al., 2013; Wei et al., 2013; Yang et al., 2014d; Huang et al., 2014c;Geiger et al., 2014; Takahashi et al., 2015). TPX2 is a potentialbiomarker for early diagnosis and prognosis of hepatocellular carcinomaand for prognosis of high-grade serous epithelial ovarian cancer andcolon cancer (Wei et al., 2013; Caceres-Gorriti et al., 2014; Liang etal., 2015a).

TRIM6 was shown to regulate the transcriptional activity of theproto-oncogene Myc (Sato et al., 2012b).

TRIP13 was shown to promote Mad2 localization to unattached kinetochoresin the spindle checkpoint response (Nelson et al., 2015). TRIP13over-expression was described as a hallmark of cancer cells showingchromosomal instability (Wang et al., 2014d). Premature mitoticcheckpoint silencing triggered by TRIP13 over-expression was suggestedto promote cancer development (Wang et al., 2014d). TRIP13 was shown tobe involved in modulating tumor cell motility in breast cancer (Maurizioet al., 2016). High expression of TRIP13 in squamous cell carcinoma ofthe head and neck was shown to lead to aggressive, treatment-resistanttumors and enhanced repair of DNA damage and promoted error-pronenon-homologous end joining (Banerjee et al., 2014). TRIP13 was describedas a putative marker of prostate cancer progression which can be used topredict recurrence in prostate cancer when combined with pre-operativePSA level and Gleason score (Larkin et al., 2012). TRIP13 was describedas one of several genes evidencing high genomic copy number changes inearly-stage non-small cell lung cancer (Kang et al., 2008a).

Recent studies have implicated TRPS1 in several human cancers such asbreast cancer, colon cancer, osteosarcoma, leukemia, endometrial cancerand prostate cancer (Chang et al., 2004; Asou et al., 2007; Chen et al.,2010; Liang et al., 2012a; Hong et al., 2013; Li et al., 2015f). Inaddition, TRPS1 expression was correlated significantly with improvedsurvival in patients with breast cancer (Chen et al., 2010).Furthermore, over-expression of TRPS1 induced angiogenesis by affectingthe expression of vascular endothelial growth factor in breast cancer(Hu et al., 2014).

Mutations in the TRRAP gene were found in colorectal cancer and inmelanoma, whereas in thyroid and ovarian cancers mutations in the TRRAPgene were absent (Wei et al., 2011; Murugan et al., 2013; Mouradov etal., 2014; Zou et al., 2015). Furthermore, knockdown of TRRAP resultedin a decreased self-renewal of cultured brain tumor-initiating cells andsensitized the cells to temozolomide-induced apoptosis (Wurdak et al.,2010).

A single nucleotide polymorphism of the TSC2 gene was significantlyassociated with colon cancer. Furthermore, down-regulation of TSC2 wasobserved in patients suffering from hepatocellular carcinoma and acutemyeloid leukemia. In one case, a mutation in the TSC2 gene seemed to beresponsible for pancreatic neuroendocrine tumors. Others have notedelevated levels of phosphorylated TSC2 in non-small cell lung carcinoma(Xu et al., 2009; Yoshizawa et al., 2010; Slattery et al., 2010;Bombardieri et al., 2013; Huynh et al., 2015). Recent work hasdemonstrated that expression of TSC2 in ERC-18 cells increasessusceptibility to apoptosis induced by OKA and thephosphatidylinositol-3′ kinase inhibitor LY294002 (Kolb et al., 2005).

TSEN15 is a target of miRNA-449a, which functions as a tumor suppressorin neuroblastoma. TSEN15 plays an important role in mediating thedifferentiation-inducing function of miRNA-449a (Zhao et al., 2015c).TSEN15 is associated with cell differentiation potential in human fetalfemur-derived cells (Mirmalek-Sani et al., 2009).

TSGA13 was shown to be down-regulated in most types of human carcinomatissues compared to adjacent normal tissues except glioblastoma and lungcancer. Hence, an association between TSGA13 and tumor malignancy islikely (Zhao et al., 2015a).

De-regulated expression of TUBA1A and some other genes, caused bychromosomal rearrangements in radiation-transformed and tumorigenicbreast cell lines, might reflect early molecular events in breastcarcinogenesis (Unger et al., 2010). Using comparative proteomicanalysis of advanced serous epithelial ovarian carcinoma, TUBA1A wasidentified as one potential predictor for chemoresistance (Kim et al.,2011c).

The differential expression of TUBA1B in combination with the expressionof some other genes was associated with prognosis in mantle celllymphoma, prediction of relapse among patients with stage II colorectalcancer and differentiation between uveal melanomas that subsequentlymetastasized and those that did not (Blenk et al., 2008; Agesen et al.,2012; Linge et al., 2012). TUBA1B expression was up-regulated inhepatocellular cancer tissues and proliferating hepatocellular cancercells. An increased TUBA1B expression was associated with poor overallsurvival and resistance to paclitaxel of hepatocellular cancer patients(Lu et al., 2013). In ovarian cancer cells, the reduced expression ofTUBA1B was associated with oxaliplatin resistance (Tummala et al.,2009). The expression of TUBA1C was shown to be up-regulated inosteosarcoma and HCV-associated hepatocellular cancer and may be apotential biomarker for osteosarcoma tumorigenesis orwell-differentiated HCV-associated hepatocellular cancer (Li et al.,2010; Kuramitsu et al., 2011).

The comparative proteomic analysis of esophageal squamous cell carcinoma(ESCC) showed an increased expression of TUBA4A (Qi et al., 2005).

In mouse liver, TUBA8 was induced after treatment with phenobarbital, anon-genotoxic carcinogen. In hepatocellular carcinoma cell lines, theover-expression of TUBA8 was shown to affect cell growth, proliferationand migration (Kamino et al., 2011).

Several publications have observed over-expression of TYK2 in humanbreast cancer cell lines, as well as in prostate cancers and squamouscervical carcinomas. In contrast, lack of TYK2 in mice has been linkedto the development of Abelson-induced B lymphoid leukemia and lymphoma.In addition, single nucleotide polymorphism in the TYK2 gene has beenassociated with rectal cancer (Stoiber et al., 2004; Ide et al., 2008;Song et al., 2008; Zhu et al., 2009; Slattery et al., 2013). In prostatecancer cell lines, suppression of Tyk2 with siRNA inhibited the abilityof these cells to migrate (Ide et al., 2008).

Recent work has identified a gain in copy number of the UBE2H gene inhepatocellular carcinoma. Others have observed an increase in the levelsof UBE2H in breast cancer, whereas this was not the case in colon cancer(Chen and Madura, 2005; Keng et al., 2009).

Down-regulation of UBE2L6 has been observed in nasopharyngeal carcinoma,whereas in esophageal squamous cell carcinoma UBE2L6 was over-expressed(Dadkhah et al., 2013; Zhou et al., 2015a). In addition, low levels ofUBE2L6 have been linked with poor outcome in patients suffering fromnasopharyngeal carcinoma (Zhou et al., 2015a). Moreover, UBE2L6 has beenshown to disrupt F-actin architecture and formation of focal adhesionsin breast cancer cell lines as well as promoting cell migration.Furthermore, restored expression of UBE2L6 suppressed proliferation andcolony formation in nasopharyngeal carcinoma cells, while at the sametime inducing apoptosis (Desai et al., 2012; Zhou et al., 2015a).Researchers have postulated that UBE2L6 could be used as a biomarker oftreatment response to bortezomib in patients with acute promyelocyticleukemia (Takenokuchi et al., 2015).

Elevated levels of UBE2V1 expression were detected in breast cancersamples as well as in cultured tumor cell lines. Moreover, UBE2V1 genehas been identified to be associated with the development of prostatecancer (Stubbs et al., 1999; Xiao et al., 1998; Tanner et al., 1995).Researchers have shown that UBE2V1 induced cell migration and invasionin breast cancer. Similarly, high levels of UBE2V1 promoted tumor growthand metastasis in a xenograft mouse model. NSC697923, an inhibitor ofUBE2V1 was able to inhibit proliferation and survival of diffuse largeB-cell lymphoma cells (Pulvino et al., 2012; Wu et al., 2014b).

Some researchers have observed over-expression of UBE3C in clear-cellrenal cell carcinoma tissues compared with adjacent normal tissues.Others have also found elevated levels of UBE3C in hepatocellularcarcinoma. In addition, up-regulation of UBE3C gene was reported inmyeloma side-population cells (Jiang et al., 2014a; Tagawa, 2014; Wen etal., 2015). Furthermore, over-expression of UBE3C in hepatocellularcarcinoma tissues was associated with decreased survival and early tumorrecurrence in post-operative hepatocellular carcinoma patients (Jiang etal., 2014a).

Researchers have identified a mutation in the UBE4B gene in a patientsuffering from neuroblastoma. Genome-wide association study revealedthat the UBE4B gene might be involved in hepatitis B virus-relatedhepatocellular carcinoma. Others reported over-expression of UBE4B inbreast cancer and in brain tumors (Krona et al., 2003; Zhang et al.,2010b; Wu et al., 2011 b; Zhang et al., 2014f). Moreover,down-regulation of UBE4B was correlated with poor outcome in patientswith neuroblastoma (Zage et al., 2013). UBR4 was shown to be associatedwith invasive micropapillary carcinoma of the breast (Gruel et al.,2014).

UNC45A was shown to be up-regulated in breast carcinoma and ovariancarcinoma (Guo et al., 2011; Bazzaro et al., 2007). UNC45A is associatedwith metastasis in breast cancer (Guo et al., 2011). UNC45A isassociated with drug resistance in neuroblastoma (Epping et al., 2009).

Novel germline sequence variations in UNG were detected in patientsaffected by colorectal cancer with familial aggregation, emphasizingthat these variants could be involved in disease susceptibility. Inaddition, UNG activity in colorectal tissue appeared to be higher intumor tissue compared to normal bowel (Dusseau et al., 2001; Brodericket al., 2006; Marian et al., 2011; Yin et al., 2014). Furthermore,knockdown of UNG induced apoptosis in prostate cancer cell lines,reduced cell proliferation and increased cellular sensitivity togenotoxic stress. Others have observed that colon cancer cells lackingUNG are hypersensitive to pemetrexed-induced uracil accumulation, whichleads to cell cycle arrest, DNA double strand break formation andapoptosis (Pulukuri et al., 2009; Weeks et al., 2013).

UQCR11 is associated with renal cell carcinoma (Sarto et al., 1997).

USP11 plays a major role in promyelocytic leukemia and pancreatic cancer(Burkhart et al., 2013; Wu et al., 2014a).

USP28 was shown to be up-regulated in intestinal cancer, bladder cancer,colon carcinoma and breast carcinoma (Guo et al., 2014; Diefenbacher etal., 2014; Popov et al., 2007). USP28 is associated with colorectalcancer and breast cancer (Wu et al., 2013b; Diefenbacher et al., 2014).USP28 over-expression is associated with low survival and poor prognosisin non-small cell lung cancer patients (Zhang et al., 2015i). USP28 is apotential prognostic marker for bladder cancer (Guo et al., 2014).

Several publications have found an association between USP9X and varioustypes of cancer including, breast cancer, lung cancer, colon cancer,non-small cell lung cancer and low grade serous ovarian tumors (Deng etal., 2007; Peddaboina et al., 2012; Peng et al., 2015b; Hunter et al.,2015). Furthermore, elevated levels of USP9X were correlated withpositive lymph node metastasis, clinical stage and a reduced overallsurvival rate in patients affected by non-small cell lung cancer (Wanget al., 2015j). Silencing of USP9X expression by siRNA resulted in cellapoptosis, inhibited cell growth and cell migration in hepatocellularcarcinoma cell lines (Hu et al., 2015).

Over-expression of USP9Y has been observed in breast cancer and prostatecancer. Recently, a USP9Y-TTTY15 fusion was identified in a Chinesepopulation suffering from prostate cancer. However, others havedemonstrated that the USP9Y-TTTY15 fusion is not specific to prostatecancer, but it was also found in non-malignant prostate tissues as wellas non-malignant tissue from other organs (Deng et al., 2007; Dasari etal., 2001; Ren et al., 2012; Ren et al., 2014).

VCPIP1 was shown to be associated with breast cancer (Kuznetsova et al.,2007). VCPIP1 is down-regulated in breast cancer (Kuznetsova et al.,2007). VCPIP1 is one of the de-ubiquitinating enzymes, being part of theovarian tumor family (OTU) (Enesa and Evans, 2014).

In lung adenocarcinoma patients, VPRBP was correlated with poorprognosis (Wang et al., 2013a). Others have revealed thatdown-regulation of VPRBP-mediated phosphorylation of Histone 2A(H2AT120p) impeded cancer cell proliferation and xenograft tumorprogression (Kim et al., 2013b).

VPS13D was shown to be a phosphopeptide relevant for the oncogenicphosphatidylinositol 3-kinase (PI3K) pathway which can be regulated byPI3K pathway inhibiting drugs (Andersen et al., 2010).

VTCN1 was shown to be up-regulated in lung cancer, colorectal cancer,hepatocellular carcinoma, osteosarcoma, breast cancer, cervical cancer,urothelial cell carcinoma, gastric cancer, endometrial cancer, thyroidcancer and laryngeal carcinoma (Klatka et al., 2013; Zhu et al., 2013b;Vanderstraeten et al., 2014; Shi et al., 2014b; Fan et al., 2014; Wanget al., 2014g; Leong et al., 2015; Dong and Ma, 2015; Zhang et al.,2015a; Peng et al., 2015a; Xu et al., 2015a). VTCN1 is associated withpoor overall survival and higher recurrence probability inhepatocellular carcinoma and poor overall survival in osteosarcoma,urothelial cell carcinoma, pancreatic cancer, gastric cancer, cervicalcancer, melanoma and thyroid cancer (Zhu et al., 2013b; Seliger, 2014;Liu et al., 2014f; Chen et al., 2014i; Fan et al., 2014; Dong and Ma,2015; Zhang et al., 2015a). VTCN1 is associated with clear cell renalcell carcinoma (Xu et al., 2014c). VTCN1 expression levels were shown tobe inversely correlated with patient survival in ovarian cancer (Smithet al., 2014). VTCN1 may be a potential prognostic indicator ofurothelial cell carcinoma and gastric cancer (Shi et al., 2014b; Fan etal., 2014).

VWA1 is associated with clear-cell ovarian cancer (Cicek et al., 2013).

VWA2 was shown to be associated with colorectal cancer (Hoff et al.,2015). VWA2 was shown to be highly induced in stage II, III and IV coloncancers, colon adenomas and colon cancer cell lines. Thus, VWA2 is anovel candidate for development as a diagnostic serum marker of earlystage colon cancer (Xin et al., 2005).

VWA3A was shown to be associated with survival in ovarian cancer (Maddenet al., 2014).

VWDE is mutated and shows an oncogenic character in breast cancerpatients (Pongor et al., 2015).

WDFY3 was shown to be down-regulated in colorectal cancer (Piepoli etal., 2012).

Recent studies have observed elevated levels of WHSC1 protein in severaltypes of human cancers such as carcinomas of the gastrointestinal tract(esophagus, stomach, colon, anal canal), small cell lung carcinoma,prostate cancer and tumors of the urinary bladder, female genitals andskin. Others have reported that WHSC1 over-expression resulting fromchromosomal translocation significantly affected the tumorigenicity ofmultiple myeloma cells in a xenograft model (Lauring et al., 2008;Hudlebusch et al., 2011; Yang et al., 2012d). Knock-down of WHSC1 inprostate cancer cell lines resulted in a reduction of cellproliferation, colony formation in soft agar as well as decreased cellmigration and invasion. Similarly, in squamous cell carcinoma of thehead and neck cell knock-down of WHSC1 resulted in significant growthsuppression, induction of apoptosis, and delay of the cell-cycleprogression. Furthermore, WHSC1 expression has been shown to inducecellular adhesion, clonogenic growth and tumorigenicity in multiplemyeloma (Kassambara et al., 2009; Ezponda et al., 2013; Saloura et al.,2015).

Single nucleotide polymorphisms of the WRN gene have been associatedwith the risk of breast cancer both in a German and Australianpopulation. Others have found a correlation between single nucleotidepolymorphisms of the WRN gene and susceptibility for colorectal,prostate and esophageal cancers. In addition, aberrant methylation ofWRN was observed in specimens of cervical cancer (Wirtenberger et al.,2006; Wang et al., 2011; Li et al., 2012d; Masuda et al., 2012; Sun etal., 2015d; Zins et al., 2015). Furthermore, siRNA-mediated silencing ofWRN gene suppressed carcinoma cell growth in vitro (Arai et al., 2011).

Accumulating evidence reveals that the WT1 gene is highly expressed indifferent forms of tumors including acute myeloid leukemias, acutelymphoid leukemias, hepatocellular carcinoma and squamous cell carcinomaof the head and neck (Miwa et al., 1992; Perugorria et al., 2009; Li etal., 2015d). Additionally, over-expression of WT1 is a significantpositive prognostic factor in primary high-grade serous ovariancarcinoma regarding overall survival and progression free survival.Similarly, overall survival and disease-free survival was significantlylower in acute myeloblastic leukemia patients with WT1 gene mutation.Others have also reported a correlation between the WT1 variantrs2234593 and relapse as well as overall survival in acute myeloidleukemia (Niavarani et al., 2015; Taube et al., 2016; Toogeh et al.,2016).

Some researchers have observed low XDH expression in hepatocellularcarcinomas, serous ovarian cancer and breast cancer. However, othersreported a significant increase in XDH activity in bilharzial bladdercancer and non-bilharzial bladder cancer, brain tumors and small-celland non-small cell lung cancer (Kokoglu et al., 1990; Stirpe et al.,2002; Linder et al., 2005; Kaynar et al., 2005; Metwally et al., 2011;Linder et al., 2012).

Moreover, down-regulation of XDH was reported to be associated withpoorer prognosis in patients with serous ovarian cancer and breastcancer (Linder et al., 2005; Linder et al., 2012).

XPO4 expression is down-regulated by promoter methylation inhepatocellular cancer and associated with tumor size, histopathologicalclassification and a significantly poor prognosis of patient's survival(Liang et al., 2011; Zhang et al., 2014a). Mutation of the catalyticsubunit of the PI3K leads to a highly activated Akt/mTOR pathway anddown-regulation of the tumor suppressor genes Pten, Xpo4 and Dlc1 (Kudoet al., 2011).

YBX1 has been shown to be up-regulated in various types of cancer,including colorectal, gastric, multiple myeloma and breast cancer(Bargou et al., 1997; Chatterjee et al., 2008; Wu et al., 2012g; Yan etal., 2014b). In breast cancer, over-expression of YBX1 was neitherassociated with lymph node status nor high histological grade, but withER negativity, HER2 positivity and it had an adverse impact on 5-yearoverall survival (Wang et al., 2015g). Researchers have shown that YBX1may promote the proliferation, apoptosis resistance, invasion andmigration of colorectal cancer cells by regulatingepithelial-mesenchymal transition (Yan et al., 2014c).

The TUTase ZCCHC6 was shown to be recruited by the tumorigenesisassociated RNA-binding protein Lin28 to block let-7 biogenesis.Restoring let-7 expression in cancer through TUTase inhibitors could beexploited in future drug discovery (Lin and Gregory, 2015).

ZNF583 was described as a potential biomarker for colorectal cancer(Mori et al., 2011).

ZNF700 was shown to be a capture antigen for the detection ofautoantibodies in colorectal cancer. In a panel with other zinc fingerproteins, ZNF-specific autoantibody detection allowed the detection ofcolorectal cancer (O'Reilly et al., 2015).

ZNFX1 could function as a novel prostate cancer antigen (Dunphy andMcNeel, 2005).

ZRANB2 has been shown to be over-expressed in grade III ovarian serouspapillary carcinoma (Schaner et al., 2003; Mangs and Morris, 2008).

ZWINT was shown to be associated with the arrest of prostate cancer cellcycle progression upon inhibition of COX-2 (Bieniek et al., 2014). ZWINTexpression in chronic lymphocytic leukemia cells in lymph nodes wasshown to be correlated with clinical outcome (Gilling et al., 2012).ZWINT was described as an androgen receptor target gene which was shownto be up-regulated in castration-resistant prostate cancer (Urbanucci etal., 2012). ZWINT was described as a gene of particular predictive valuein a prognostic model of pulmonary adenocarcinoma (Endoh et al., 2004).

ZYG11A serves as an oncogene in non-small cell lung cancer andinfluences CCNE1 expression (Wang et al., 2016b).

ZZEF1 was described to be potentially linked to cancer and is located ina chromosome region associated with medulloblastomas (Cvekl, Jr. et al.,2004).

DETAILED DESCRIPTION OF THE INVENTION

Stimulation of an immune response is dependent upon the presence ofantigens recognized as foreign by the host immune system. The discoveryof the existence of tumor associated antigens has raised the possibilityof using a host's immune system to intervene in tumor growth. Variousmechanisms of harnessing both the humoral and cellular arms of theimmune system are currently being explored for cancer immunotherapy.

Specific elements of the cellular immune response are capable ofspecifically recognizing and destroying tumor cells. The isolation ofT-cells from tumor-infiltrating cell populations or from peripheralblood suggests that such cells play an important role in natural immunedefense against cancer. CD8-positive T-cells in particular, whichrecognize class I molecules of the major histocompatibility complex(MHC)-bearing peptides of usually 8 to 10 amino acid residues derivedfrom proteins or defect ribosomal products (DRIPS) located in thecytosol, play an important role in this response. The MHC-molecules ofthe human are also designated as human leukocyte-antigens (HLA).

As used herein and except as noted otherwise all terms are defined asgiven below.

The term “T-cell response” means the specific proliferation andactivation of effector functions induced by a peptide in vitro or invivo. For MHC class I restricted cytotoxic T cells, effector functionsmay be lysis of peptide-pulsed, peptide-precursor pulsed or naturallypeptide-presenting target cells, secretion of cytokines, preferablyInterferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion ofeffector molecules, preferably granzymes or perforins induced bypeptide, or degranulation.

The term “peptide” is used herein to designate a series of amino acidresidues, connected one to the other typically by peptide bonds betweenthe alpha-amino and carbonyl groups of the adjacent amino acids. Thepeptides are preferably 9 amino acids in length, but can be as short as8 amino acids in length, and as long as 10, 11, 12, 13, or 14 or longer,and in case of MHC class II peptides (elongated variants of the peptidesof the invention) they can be as long as 15, 16, 17, 18, 19 or 20 ormore amino acids in length.

Furthermore, the term “peptide” shall include salts of a series of aminoacid residues, connected one to the other typically by peptide bondsbetween the alpha-amino and carbonyl groups of the adjacent amino acids.Preferably, the salts are pharmaceutical acceptable salts of thepeptides, such as, for example, the chloride or acetate(trifluoroacetate) salts. It has to be noted that the salts of thepeptides according to the present invention differ substantially fromthe peptides in their state(s) in vivo, as the peptides are not salts invivo.

The term “peptide” shall also include “oligopeptide”. The term“oligopeptide” is used herein to designate a series of amino acidresidues, connected one to the other typically by peptide bonds betweenthe alpha-amino and carbonyl groups of the adjacent amino acids. Thelength of the oligopeptide is not critical to the invention, as long asthe correct epitope or epitopes are maintained therein. Theoligopeptides are typically less than about 30 amino acid residues inlength, and greater than about 15 amino acids in length.

The term “polypeptide” designates a series of amino acid residues,connected one to the other typically by peptide bonds between thealpha-amino and carbonyl groups of the adjacent amino acids. The lengthof the polypeptide is not critical to the invention as long as thecorrect epitopes are maintained. In contrast to the terms peptide oroligopeptide, the term polypeptide is meant to refer to moleculescontaining more than about 30 amino acid residues.

A peptide, oligopeptide, protein or polynucleotide coding for such amolecule is “immunogenic” (and thus is an “immunogen” within the presentinvention), if it is capable of inducing an immune response. In the caseof the present invention, immunogenicity is more specifically defined asthe ability to induce a T-cell response. Thus, an “immunogen” would be amolecule that is capable of inducing an immune response, and in the caseof the present invention, a molecule capable of inducing a T-cellresponse. In another aspect, the immunogen can be the peptide, thecomplex of the peptide with MHC, oligopeptide, and/or protein that isused to raise specific antibodies or TCRs against it.

A class I T cell “epitope” requires a short peptide that is bound to aclass I MHC receptor, forming a ternary complex (MHC class I alphachain, beta-2-microglobulin, and peptide) that can be recognized by a Tcell bearing a matching T-cell receptor binding to the MHC/peptidecomplex with appropriate affinity. Peptides binding to MHC class Imolecules are typically 8-14 amino acids in length, and most typically 9amino acids in length.

In humans there are three different genetic loci that encode MHC class Imolecules (the MHC-molecules of the human are also designated humanleukocyte antigens (HLA)): HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02,and HLA-B*07 are examples of different MHC class I alleles that can beexpressed from these loci.

TABLE 6 Expression frequencies F of HLA-A*02 and HLA-A*24 and the mostfrequent HLA-DR serotypes. Frequencies are deduced from haplotypefrequencies Gf within the American population adapted from Mori et al.(Mori et al., 1997) employing the Hardy-Weinberg formula F = 1 − (1 −Gf)². Combinations of A*02 or A*24 with certain HLA-DR alleles might beenriched or less frequent than expected from their single frequenciesdue to linkage disequilibrium. For details refer to Chanock et al.(Chanock et al., 2004). Calculated phenotype from Allele Populationallele frequency A*02 Caucasian (North America) 49.1% A*02 AfricanAmerican (North America) 34.1% A*02 Asian American (North America) 43.2%A*02 Latin American (North American) 48.3% DR1 Caucasian (North America)19.4% DR2 Caucasian (North America) 28.2% DR3 Caucasian (North America)20.6% DR4 Caucasian (North America) 30.7% DR5 Caucasian (North America)23.3% DR6 Caucasian (North America) 26.7% DR7 Caucasian (North America)24.8% DR8 Caucasian (North America)  5.7% DR9 Caucasian (North America) 2.1% DR1 African (North) American 13.20% DR2 African (North) American29.80% DR3 African (North) American 24.80% DR4 African (North) American11.10% DR5 African (North) American 31.10% DR6 African (North) American33.70% DR7 African (North) American 19.20% DR8 African (North) American12.10% DR9 African (North) American  5.80% DR1 Asian (North) American 6.80% DR2 Asian (North) American 33.80% DR3 Asian (North) American 9.20% DR4 Asian (North) American 28.60% DR5 Asian (North) American30.00% DR6 Asian (North) American 25.10% DR7 Asian (North) American13.40% DR8 Asian (North) American 12.70% DR9 Asian (North) American18.60% DR1 Latin (North) American 15.30% DR2 Latin (North) American21.20% DR3 Latin (North) American 15.20% DR4 Latin (North) American36.80% DR5 Latin (North) American 20.00% DR6 Latin (North) American31.10% DR7 Latin (North) American 20.20% DR8 Latin (North) American18.60% DR9 Latin (North) American  2.10% A*24 Philippines    65% A*24Russia Nenets    61% A*24:02 Japan    59% A*24 Malaysia    58% A*24:02Philippines    54% A*24 India    47% A*24 South Korea    40% A*24 SriLanka    37% A*24 China    32% A*24:02 India    29% A*24 Australia West   22% A*24 USA    22% A*24 Russia Samara    20% A*24 South America   20% A*24 Europe    18%

The peptides of the invention, preferably when included into a vaccineof the invention as described herein bind to A*02. A vaccine may alsoinclude pan-binding MHC class II peptides. Therefore, the vaccine of theinvention can be used to treat cancer in patients that are A*02positive, whereas no selection for MHC class II allotypes is necessarydue to the pan-binding nature of these peptides.

If A*02 peptides of the invention are combined with peptides binding toanother allele, for example A*24, a higher percentage of any patientpopulation can be treated compared with addressing either MHC class Iallele alone. While in most populations less than 50% of patients couldbe addressed by either allele alone, a vaccine comprising HLA-A*24 andHLA-A*02 epitopes can treat at least 60% of patients in any relevantpopulation. Specifically, the following percentages of patients will bepositive for at least one of these alleles in various regions: USA 61%,Western Europe 62%, China 75%, South Korea 77%, Japan 86% (calculatedfrom www.allelefrequencies.net).

In a preferred embodiment, the term “nucleotide sequence” refers to aheteropolymer of deoxyribonucleotides.

The nucleotide sequence coding for a particular peptide, oligopeptide,or polypeptide may be naturally occurring or they may be syntheticallyconstructed. Generally, DNA segments encoding the peptides,polypeptides, and proteins of this invention are assembled from cDNAfragments and short oligonucleotide linkers, or from a series ofoligonucleotides, to provide a synthetic gene that is capable of beingexpressed in a recombinant transcriptional unit comprising regulatoryelements derived from a microbial or viral operon.

As used herein the term “a nucleotide coding for (or encoding) apeptide” refers to a nucleotide sequence coding for the peptideincluding artificial (man-made) start and stop codons compatible for thebiological system the sequence is to be expressed by, for example, adendritic cell or another cell system useful for the production of TCRs.

As used herein, reference to a nucleic acid sequence includes bothsingle stranded and double stranded nucleic acid. Thus, for example forDNA, the specific sequence, unless the context indicates otherwise,refers to the single strand DNA of such sequence, the duplex of suchsequence with its complement (double stranded DNA) and the complement ofsuch sequence.

The term “coding region” refers to that portion of a gene which eithernaturally or normally codes for the expression product of that gene inits natural genomic environment, i.e., the region coding in vivo for thenative expression product of the gene.

The coding region can be derived from a non-mutated (“normal”), mutatedor altered gene, or can even be derived from a DNA sequence, or gene,wholly synthesized in the laboratory using methods well known to thoseof skill in the art of DNA synthesis.

The term “expression product” means the polypeptide or protein that isthe natural translation product of the gene and any nucleic acidsequence coding equivalents resulting from genetic code degeneracy andthus coding for the same amino acid(s).

The term “fragment”, when referring to a coding sequence, means aportion of DNA comprising less than the complete coding region, whoseexpression product retains essentially the same biological function oractivity as the expression product of the complete coding region.

The term “DNA segment” refers to a DNA polymer, in the form of aseparate fragment or as a component of a larger DNA construct, which hasbeen derived from DNA isolated at least once in substantially pure form,i.e., free of contaminating endogenous materials and in a quantity orconcentration enabling identification, manipulation, and recovery of thesegment and its component nucleotide sequences by standard biochemicalmethods, for example, by using a cloning vector. Such segments areprovided in the form of an open reading frame uninterrupted by internalnon-translated sequences, or introns, which are typically present ineukaryotic genes. Sequences of non-translated DNA may be presentdownstream from the open reading frame, where the same do not interferewith manipulation or expression of the coding regions.

The term “primer” means a short nucleic acid sequence that can be pairedwith one strand of DNA and provides a free 3′-OH end at which a DNApolymerase starts synthesis of a deoxyribonucleotide chain.

The term “promoter” means a region of DNA involved in binding of RNApolymerase to initiate transcription.

The term “isolated” means that the material is removed from its originalenvironment (e.g., the natural environment, if it is naturallyoccurring). For example, a naturally-occurring polynucleotide orpolypeptide present in a living animal is not isolated, but the samepolynucleotide or polypeptide, separated from some or all of thecoexisting materials in the natural system, is isolated. Suchpolynucleotides could be part of a vector and/or such polynucleotides orpolypeptides could be part of a composition, and still be isolated inthat such vector or composition is not part of its natural environment.

The polynucleotides, and recombinant or immunogenic polypeptides,disclosed in accordance with the present invention may also be in“purified” form. The term “purified” does not require absolute purity;rather, it is intended as a relative definition, and can includepreparations that are highly purified or preparations that are onlypartially purified, as those terms are understood by those of skill inthe relevant art. For example, individual clones isolated from a cDNAlibrary have been conventionally purified to electrophoretichomogeneity. Purification of starting material or natural material to atleast one order of magnitude, preferably two or three orders, and morepreferably four or five orders of magnitude is expressly contemplated.Furthermore, a claimed polypeptide which has a purity of preferably99.999%, or at least 99.99% or 99.9%; and even desirably 99% by weightor greater is expressly encompassed.

The nucleic acids and polypeptide expression products disclosedaccording to the present invention, as well as expression vectorscontaining such nucleic acids and/or such polypeptides, may be in“enriched form”. As used herein, the term “enriched” means that theconcentration of the material is at least about 2, 5, 10, 100, or 1000times its natural concentration (for example), advantageously 0.01%, byweight, preferably at least about 0.1% by weight. Enriched preparationsof about 0.5%, 1%, 5%, 10%, and 20% by weight are also contemplated. Thesequences, constructs, vectors, clones, and other materials comprisingthe present invention can advantageously be in enriched or isolatedform. The term “active fragment” means a fragment, usually of a peptide,polypeptide or nucleic acid sequence, that generates an immune response(i.e., has immunogenic activity) when administered, alone or optionallywith a suitable adjuvant or in a vector, to an animal, such as a mammal,for example, a rabbit or a mouse, and also including a human, suchimmune response taking the form of stimulating a T-cell response withinthe recipient animal, such as a human. Alternatively, the “activefragment” may also be used to induce a T-cell response in vitro.

As used herein, the terms “portion”, “segment” and “fragment”, when usedin relation to polypeptides, refer to a continuous sequence of residues,such as amino acid residues, which sequence forms a subset of a largersequence. For example, if a polypeptide were subjected to treatment withany of the common endopeptidases, such as trypsin or chymotrypsin, theoligopeptides resulting from such treatment would represent portions,segments or fragments of the starting polypeptide. When used in relationto polynucleotides, these terms refer to the products produced bytreatment of said polynucleotides with any of the endonucleases.

In accordance with the present invention, the term “percent identity” or“percent identical”, when referring to a sequence, means that a sequenceis compared to a claimed or described sequence after alignment of thesequence to be compared (the “Compared Sequence”) with the described orclaimed sequence (the “Reference Sequence”). The percent identity isthen determined according to the following formula:percent identity=100[1−(C/R)]wherein C is the number of differences between the Reference Sequenceand the Compared Sequence over the length of alignment between theReference Sequence and the Compared Sequence, wherein

(i) each base or amino acid in the Reference Sequence that does not havea corresponding aligned base or amino acid in the Compared Sequence and

(ii) each gap in the Reference Sequence and

(iii) each aligned base or amino acid in the Reference Sequence that isdifferent from an aligned base or amino acid in the Compared Sequence,constitutes a difference and

(iiii) the alignment has to start at position 1 of the alignedsequences;

and R is the number of bases or amino acids in the Reference Sequenceover the length of the alignment with the Compared Sequence with any gapcreated in the Reference Sequence also being counted as a base or aminoacid.

If an alignment exists between the Compared Sequence and the ReferenceSequence for which the percent identity as calculated above is aboutequal to or greater than a specified minimum Percent Identity, then theCompared Sequence has the specified minimum percent identity to theReference Sequence even though alignments may exist in which the hereinabove calculated percent identity is less than the specified percentidentity.

As mentioned above, the present invention thus provides a peptidecomprising a sequence that is selected from the group of consisting ofSEQ ID NO: 1 to SEQ ID NO: 640 or a variant thereof which is 88%homologous to SEQ ID NO: 1 to SEQ ID NO: 640, or a variant thereof thatwill induce T cells cross-reacting with said peptide. The peptides ofthe invention have the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class-I or elongated versions of saidpeptides to class II.

In the present invention, the term “homologous” refers to the degree ofidentity (see percent identity above) between sequences of two aminoacid sequences, i.e. peptide or polypeptide sequences. Theaforementioned “homology” is determined by comparing two sequencesaligned under optimal conditions over the sequences to be compared. Sucha sequence homology can be calculated by creating an alignment using,for example, the ClustalW algorithm. Commonly available sequenceanalysis software, more specifically, Vector NTI, GENETYX or other toolsare provided by public databases.

A person skilled in the art will be able to assess, whether T cellsinduced by a variant of a specific peptide will be able to cross-reactwith the peptide itself (Appay et al., 2006; Colombetti et al., 2006;Fong et al., 2001; Zaremba et al., 1997).

By a “variant” of the given amino acid sequence the inventors mean thatthe side chains of, for example, one or two of the amino acid residuesare altered (for example by replacing them with the side chain ofanother naturally occurring amino acid residue or some other side chain)such that the peptide is still able to bind to an HLA molecule insubstantially the same way as a peptide consisting of the given aminoacid sequence in consisting of SEQ ID NO: 1 to SEQ ID NO: 640. Forexample, a peptide may be modified so that it at least maintains, if notimproves, the ability to interact with and bind to the binding groove ofa suitable MHC molecule, such as HLA-A*02 or -DR, and in that way it atleast maintains, if not improves, the ability to bind to the TCR ofactivated T cells.

These T cells can subsequently cross-react with cells and kill cellsthat express a polypeptide that contains the natural amino acid sequenceof the cognate peptide as defined in the aspects of the invention. Ascan be derived from the scientific literature and databases (Rammenseeet al., 1999; Godkin et al., 1997), certain positions of HLA bindingpeptides are typically anchor residues forming a core sequence fittingto the binding motif of the HLA receptor, which is defined by polar,electrophysical, hydrophobic and spatial properties of the polypeptidechains constituting the binding groove. Thus, one skilled in the artwould be able to modify the amino acid sequences set forth in SEQ ID NO:1 to SEQ ID NO 640, by maintaining the known anchor residues, and wouldbe able to determine whether such variants maintain the ability to bindMHC class I or II molecules. The variants of the present inventionretain the ability to bind to the TCR of activated T cells, which cansubsequently cross-react with and kill cells that express a polypeptidecontaining the natural amino acid sequence of the cognate peptide asdefined in the aspects of the invention.

The original (unmodified) peptides as disclosed herein can be modifiedby the substitution of one or more residues at different, possiblyselective, sites within the peptide chain, if not otherwise stated.Preferably those substitutions are located at the end of the amino acidchain. Such substitutions may be of a conservative nature, for example,where one amino acid is replaced by an amino acid of similar structureand characteristics, such as where a hydrophobic amino acid is replacedby another hydrophobic amino acid. Even more conservative would bereplacement of amino acids of the same or similar size and chemicalnature, such as where leucine is replaced by isoleucine. In studies ofsequence variations in families of naturally occurring homologousproteins, certain amino acid substitutions are more often tolerated thanothers, and these are often show correlation with similarities in size,charge, polarity, and hydrophobicity between the original amino acid andits replacement, and such is the basis for defining “conservativesubstitutions.” Conservative substitutions are herein defined asexchanges within one of the following five groups: Group 1-smallaliphatic, nonpolar or slightly polar residues (Ala, Ser, Thr, Pro,Gly); Group 2-polar, negatively charged residues and their amides (Asp,Asn, Glu, Gln); Group 3-polar, positively charged residues (His, Arg,Lys); Group 4-large, aliphatic, nonpolar residues (Met, Leu, lie, Val,Cys); and Group 5-large, aromatic residues (Phe, Tyr, Trp).

Less conservative substitutions might involve the replacement of oneamino acid by another that has similar characteristics but is somewhatdifferent in size, such as replacement of an alanine by an isoleucineresidue. Highly non-conservative replacements might involve substitutingan acidic amino acid for one that is polar, or even for one that isbasic in character. Such “radical” substitutions cannot, however, bedismissed as potentially ineffective since chemical effects are nottotally predictable and radical substitutions might well give rise toserendipitous effects not otherwise predictable from simple chemicalprinciples.

Of course, such substitutions may involve structures other than thecommon L-amino acids. Thus, D-amino acids might be substituted for theL-amino acids commonly found in the antigenic peptides of the inventionand yet still be encompassed by the disclosure herein. In addition,non-standard amino acids (i.e., other than the common naturallyoccurring proteinogenic amino acids) may also be used for substitutionpurposes to produce immunogens and immunogenic polypeptides according tothe present invention.

If substitutions at more than one position are found to result in apeptide with substantially equivalent or greater antigenic activity asdefined below, then combinations of those substitutions will be testedto determine if the combined substitutions result in additive orsynergistic effects on the antigenicity of the peptide. At most, no morethan 4 positions within the peptide would be simultaneously substituted.

A peptide consisting essentially of the amino acid sequence as indicatedherein can have one or two non-anchor amino acids (see below regardingthe anchor motif) exchanged without that the ability to bind to amolecule of the human major histocompatibility complex (MHC) class-I or-II is substantially changed or is negatively affected, when compared tothe non-modified peptide. In another embodiment, in a peptide consistingessentially of the amino acid sequence as indicated herein, one or twoamino acids can be exchanged with their conservative exchange partners(see herein below) without that the ability to bind to a molecule of thehuman major histocompatibility complex (MHC) class-I or -II issubstantially changed, or is negatively affected, when compared to thenon-modified peptide.

The amino acid residues that do not substantially contribute tointeractions with the T-cell receptor can be modified by replacementwith other amino acids whose incorporation does not substantially affectT-cell reactivity and does not eliminate binding to the relevant MHC.Thus, apart from the proviso given, the peptide of the invention may beany peptide (by which term the inventors include oligopeptide orpolypeptide), which includes the amino acid sequences or a portion orvariant thereof as given.

TABLE 7 Variants and motif of the peptides according to SEQ ID NO: 20,40, and 217 Position 1 2 3 4 5 6 7 8 9 SEQ ID NO. 20 R M I E Y F I D VVariants I L A L I L L L L A A I A L A A A V I V L V V A T I T L T T A QI Q L Q Q A SEQ ID NO. 40 T L L V K V F S V Variants I L I I I I A M L MI M M A A L A I A A A V L V I V V A T L T I T T A Q L Q I Q Q A SEQ IDNO. 217 A L I H P V S T V Variants L I A M L M I M M A A L A I A A A V LV I V V A T L T I T T A Q L Q I Q Q A

Longer (elongated) peptides may also be suitable. It is possible thatMHC class I epitopes, although usually between 8 and 11 amino acidslong, are generated by peptide processing from longer peptides orproteins that include the actual epitope. It is preferred that theresidues that flank the actual epitope are residues that do notsubstantially affect proteolytic cleavage necessary to expose the actualepitope during processing.

The peptides of the invention can be elongated by up to four aminoacids, that is 1, 2, 3 or 4 amino acids can be added to either end inany combination between 4:0 and 0:4. Combinations of the elongationsaccording to the invention can be found in Table 8.

TABLE 8 Combinations of the elongations of peptides of the inventionC-terminus N-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0 or 1 or 2 or 3 0 0or 1 or 2 or 3 or 4 N-terminus C-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0or 1 or 2 or 3 0 0 or 1 or 2 or 3 or 4

The amino acids for the elongation/extension can be the peptides of theoriginal sequence of the protein or any other amino acid(s). Theelongation can be used to enhance the stability or solubility of thepeptides.

Thus, the epitopes of the present invention may be identical tonaturally occurring tumor-associated or tumor-specific epitopes or mayinclude epitopes that differ by no more than four residues from thereference peptide, as long as they have substantially identicalantigenic activity.

In an alternative embodiment, the peptide is elongated on either or bothsides by more than 4 amino acids, preferably to a total length of up to30 amino acids. This may lead to MHC class II binding peptides. Bindingto MHC class II can be tested by methods known in the art.

Accordingly, the present invention provides peptides and variants of MHCclass I epitopes, wherein the peptide or variant has an overall lengthof between 8 and 100, preferably between 8 and 30, and most preferredbetween 8 and 14, namely 8, 9, 10, 11, 12, 13, 14 amino acids, in caseof the elongated class II binding peptides the length can also be 15,16, 17, 18, 19, 20, 21 or 22 amino acids.

Of course, the peptide or variant according to the present inventionwill have the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class I or II. Binding of a peptide ora variant to a MHC complex may be tested by methods known in the art.

Preferably, when the T cells specific for a peptide according to thepresent invention are tested against the substituted peptides, thepeptide concentration at which the substituted peptides achieve half themaximal increase in lysis relative to background is no more than about 1mM, preferably no more than about 1 μM, more preferably no more thanabout 1 nM, and still more preferably no more than about 100 μM, andmost preferably no more than about 10 μM. It is also preferred that thesubstituted peptide be recognized by T cells from more than oneindividual, at least two, and more preferably three individuals.

In a particularly preferred embodiment of the invention the peptideconsists or consists essentially of an amino acid sequence according toSEQ ID NO: 1 to SEQ ID NO: 640.

“Consisting essentially of” shall mean that a peptide according to thepresent invention, in addition to the sequence according to any of SEQID NO: 1 to SEQ ID NO 640 or a variant thereof contains additional N-and/or C-terminally located stretches of amino acids that are notnecessarily forming part of the peptide that functions as an epitope forMHC molecules epitope.

Nevertheless, these stretches can be important to provide an efficientintroduction of the peptide according to the present invention into thecells. In one embodiment of the present invention, the peptide is partof a fusion protein which comprises, for example, the 80 N-terminalamino acids of the HLA-DR antigen-associated invariant chain (p33, inthe following “li”) as derived from the NCBI, GenBank Accession numberX00497. In other fusions, the peptides of the present invention can befused to an antibody as described herein, or a functional part thereof,in particular into a sequence of an antibody, so as to be specificallytargeted by said antibody, or, for example, to or into an antibody thatis specific for dendritic cells as described herein.

In addition, the peptide or variant may be modified further to improvestability and/or binding to MHC molecules in order to elicit a strongerimmune response. Methods for such an optimization of a peptide sequenceare well known in the art and include, for example, the introduction ofreverse peptide bonds or non-peptide bonds.

In a reverse peptide bond amino acid residues are not joined by peptide(—CO—NH—) linkages but the peptide bond is reversed. Such retro-inversopeptidomimetics may be made using methods known in the art, for examplesuch as those described in Meziere et al (1997) (Meziere et al., 1997),incorporated herein by reference. This approach involves makingpseudopeptides containing changes involving the backbone, and not theorientation of side chains. Meziere et al. (Meziere et al., 1997) showthat for MHC binding and T helper cell responses, these pseudopeptidesare useful. Retro-inverse peptides, which contain NH—CO bonds instead ofCO—NH peptide bonds, are much more resistant to proteolysis.

A non-peptide bond is, for example, —CH₂—NH, —CH₂S—, —CH₂CH₂—, —CH═CH—,—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—. U.S. Pat. No. 4,897,445 provides amethod for the solid phase synthesis of non-peptide bonds (—CH₂—NH) inpolypeptide chains which involves polypeptides synthesized by standardprocedures and the non-peptide bond synthesized by reacting an aminoaldehyde and an amino acid in the presence of NaCNBH₃.

Peptides comprising the sequences described above may be synthesizedwith additional chemical groups present at their amino and/or carboxytermini, to enhance the stability, bioavailability, and/or affinity ofthe peptides. For example, hydrophobic groups such as carbobenzoxyl,dansyl, or t-butyloxycarbonyl groups may be added to the peptides' aminotermini. Likewise, an acetyl group or a 9-fluorenylmethoxy-carbonylgroup may be placed at the peptides' amino termini. Additionally, thehydrophobic group, t-butyloxycarbonyl, or an amido group may be added tothe peptides' carboxy termini.

Further, the peptides of the invention may be synthesized to alter theirsteric configuration. For example, the D-isomer of one or more of theamino acid residues of the peptide may be used, rather than the usualL-isomer. Still further, at least one of the amino acid residues of thepeptides of the invention may be substituted by one of the well-knownnon-naturally occurring amino acid residues. Alterations such as thesemay serve to increase the stability, bioavailability and/or bindingaction of the peptides of the invention.

Similarly, a peptide or variant of the invention may be modifiedchemically by reacting specific amino acids either before or aftersynthesis of the peptide. Examples for such modifications are well knownin the art and are summarized e.g. in R. Lundblad, Chemical Reagents forProtein Modification, 3rd ed. CRC Press, 2004 (Lundblad, 2004), which isincorporated herein by reference. Chemical modification of amino acidsincludes but is not limited to, modification by acylation, amidination,pyridoxylation of lysine, reductive alkylation, trinitrobenzylation ofamino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS), amidemodification of carboxyl groups and sulphydryl modification by performicacid oxidation of cysteine to cysteic acid, formation of mercurialderivatives, formation of mixed disulphides with other thiol compounds,reaction with maleimide, carboxymethylation with iodoacetic acid oriodoacetamide and carbamoylation with cyanate at alkaline pH, althoughwithout limitation thereto. In this regard, the skilled person isreferred to Chapter 15 of Current Protocols In Protein Science, Eds.Coligan et al. (John Wiley and Sons NY 1995-2000) (Coligan et al., 1995)for more extensive methodology relating to chemical modification ofproteins.

Briefly, modification of e.g. arginyl residues in proteins is oftenbased on the reaction of vicinal dicarbonyl compounds such asphenylglyoxal, 2,3-butanedione, and 1,2-cyclohexanedione to form anadduct. Another example is the reaction of methylglyoxal with arginineresidues. Cysteine can be modified without concomitant modification ofother nucleophilic sites such as lysine and histidine. As a result, alarge number of reagents are available for the modification of cysteine.The websites of companies such as Sigma-Aldrich (www.sigma-aldrich.com)provide information on specific reagents.

Selective reduction of disulfide bonds in proteins is also common.Disulfide bonds can be formed and oxidized during the heat treatment ofbiopharmaceuticals. Woodward's Reagent K may be used to modify specificglutamic acid residues. N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimidecan be used to form intra-molecular crosslinks between a lysine residueand a glutamic acid residue. For example, diethylpyrocarbonate is areagent for the modification of histidyl residues in proteins.

Histidine can also be modified using 4-hydroxy-2-nonenal. The reactionof lysine residues and other α-amino groups is, for example, useful inbinding of peptides to surfaces or the cross-linking ofproteins/peptides. Lysine is the site of attachment ofpoly(ethylene)glycol and the major site of modification in theglycosylation of proteins. Methionine residues in proteins can bemodified with e.g. iodoacetamide, bromoethylamine, and chloramine T.

Tetranitromethane and N-acetylimidazole can be used for the modificationof tyrosyl residues. Cross-linking via the formation of dityrosine canbe accomplished with hydrogen peroxide/copper ions.

Recent studies on the modification of tryptophan have usedN-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or3-bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole (BPNS-skatole).

Successful modification of therapeutic proteins and peptides with PEG isoften associated with an extension of circulatory half-life whilecross-linking of proteins with glutaraldehyde, polyethylene glycoldiacrylate and formaldehyde is used for the preparation of hydrogels.Chemical modification of allergens for immunotherapy is often achievedby carbamylation with potassium cyanate.

A peptide or variant, wherein the peptide is modified or includesnon-peptide bonds is a preferred embodiment of the invention. Generally,peptides and variants (at least those containing peptide linkagesbetween amino acid residues) may be synthesized by the Fmoc-polyamidemode of solid-phase peptide synthesis as disclosed by Lukas et al.(Lukas et al., 1981) and by references as cited therein. TemporaryN-amino group protection is afforded by the 9-fluorenylmethyloxycarbonyl(Fmoc) group. Repetitive cleavage of this highly base-labile protectinggroup is done using 20% piperidine in N, N-dimethylformamide. Side-chainfunctionalities may be protected as their butyl ethers (in the case ofserine, threonine, and tyrosine), butyl esters (in the case of glutamicacid and aspartic acid), butyloxycarbonyl derivative (in the case oflysine and histidine), trityl derivative (in the case of cysteine) and4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the case ofarginine). Where glutamine or asparagine are C-terminal residues, use ismade of the 4,4′-dimethoxybenzhydryl group for protection of the sidechain amido functionalities. The solid-phase support is based on apolydimethyl-acrylamide polymer constituted from the three monomersdimethylacrylamide (backbone-monomer), bisacryloylethylene diamine(cross linker) and acryloylsarcosine methyl ester (functionalizingagent). The peptide-to-resin cleavable linked agent used is theacid-labile 4-hydroxymethyl-phenoxyacetic acid derivative. All aminoacid derivatives are added as their preformed symmetrical anhydridederivatives with the exception of asparagine and glutamine, which areadded using a reversed N, N-dicyclohexyl-carbodiimide/1hydroxybenzotriazole mediated coupling procedure. All coupling anddeprotection reactions are monitored using ninhydrin, trinitrobenzenesulphonic acid or isotin test procedures. Upon completion of synthesis,peptides are cleaved from the resin support with concomitant removal ofside-chain protecting groups by treatment with 95% trifluoroacetic acidcontaining a 50% scavenger mix. Scavengers commonly used includeethanedithiol, phenol, anisole and water, the exact choice depending onthe constituent amino acids of the peptide being synthesized. Also acombination of solid phase and solution phase methodologies for thesynthesis of peptides is possible (see, for example, (Bruckdorfer etal., 2004), and the references as cited therein).

Trifluoroacetic acid is removed by evaporation in vacuo, with subsequenttrituration with diethyl ether affording the crude peptide. Anyscavengers present are removed by a simple extraction procedure which onlyophilization of the aqueous phase affords the crude peptide free ofscavengers. Reagents for peptide synthesis are generally available frome.g. Calbiochem-Novabiochem (Nottingham, UK).

Purification may be performed by any one, or a combination of,techniques such as re-crystallization, size exclusion chromatography,ion-exchange chromatography, hydrophobic interaction chromatography and(usually) reverse-phase high performance liquid chromatography usinge.g. acetonitrile/water gradient separation.

Analysis of peptides may be carried out using thin layer chromatography,electrophoresis, in particular capillary electrophoresis, solid phaseextraction (CSPE), reverse-phase high performance liquid chromatography,amino-acid analysis after acid hydrolysis and by fast atom bombardment(FAB) mass spectrometric analysis, as well as MALDI and ESI-Q-TOF massspectrometric analysis.

In order to select over-presented peptides, a presentation profile iscalculated showing the median sample presentation as well as replicatevariation. The profile juxtaposes samples of the tumor entity ofinterest to a baseline of normal tissue samples. Each of these profilescan then be consolidated into an over-presentation score by calculatingthe p-value of a Linear Mixed-Effects Model (Pinheiro et al., 2015)adjusting for multiple testing by False Discovery Rate (Benjamini andHochberg, 1995).

For the identification and relative quantitation of HLA ligands by massspectrometry, HLA molecules from shock-frozen tissue samples werepurified and HLA-associated peptides were isolated. The isolatedpeptides were separated and sequences were identified by onlinenano-electrospray-ionization (nanoESI) liquid chromatography-massspectrometry (LC-MS) experiments. The resulting peptide sequences wereverified by comparison of the fragmentation pattern of naturaltumor-associated peptides (TUMAPs) recorded from ovarian cancer samples(N=20 A*02-positive samples) with the fragmentation patterns ofcorresponding synthetic reference peptides of identical sequences. Sincethe peptides were directly identified as ligands of HLA molecules ofprimary tumors, these results provide direct evidence for the naturalprocessing and presentation of the identified peptides on primary cancertissue obtained from 20 ovarian cancer patients.

The discovery pipeline XPRESIDENT® v2.1 (see, for example, US2013-0096016, which is hereby incorporated by reference in its entirety)allows the identification and selection of relevant over-presentedpeptide vaccine candidates based on direct relative quantitation ofHLA-restricted peptide levels on cancer tissues in comparison to severaldifferent non-cancerous tissues and organs. This was achieved by thedevelopment of label-free differential quantitation using the acquiredLC-MS data processed by a proprietary data analysis pipeline, combiningalgorithms for sequence identification, spectral clustering, ioncounting, retention time alignment, charge state deconvolution andnormalization.

Presentation levels including error estimates for each peptide andsample were established. Peptides exclusively presented on tumor tissueand peptides over-presented in tumor versus non-cancerous tissues andorgans have been identified.

HLA-peptide complexes from ovarian cancer tissue samples were purifiedand HLA-associated peptides were isolated and analyzed by LC-MS (seeexamples). All TUMAPs contained in the present application wereidentified with this approach on primary ovarian cancer samplesconfirming their presentation on primary ovarian cancer.

TUMAPs identified on multiple ovarian cancer and normal tissues werequantified using ion-counting of label-free LC-MS data. The methodassumes that LC-MS signal areas of a peptide correlate with itsabundance in the sample. All quantitative signals of a peptide invarious LC-MS experiments were normalized based on central tendency,averaged per sample and merged into a bar plot, called presentationprofile. The presentation profile consolidates different analysismethods like protein database search, spectral clustering, charge statedeconvolution (decharging) and retention time alignment andnormalization. Furthermore, the discovery pipeline XPRESIDENT® v2.xallows the direct absolute quantitation of MHC-, preferablyHLA-restricted, peptide levels on cancer or other infected tissues.Briefly, the total cell count was calculated from the total DNA contentof the analyzed tissue sample. The total peptide amount for a TUMAP in atissue sample was measured by nanoLC-MS/MS as the ratio of the naturalTUMAP and a known amount of an isotope-labelled version of the TUMAP,the so-called internal standard. The efficiency of TUMAP isolation wasdetermined by spiking peptide:MHC complexes of all selected TUMAPs intothe tissue lysate at the earliest possible point of the TUMAP isolationprocedure and their detection by nanoLC-MS/MS following completion ofthe peptide isolation procedure. The total cell count and the amount oftotal peptide were calculated from triplicate measurements per tissuesample. The peptide-specific isolation efficiencies were calculated asan average from 10 spike experiments each measured as a triplicate (seeExample 6 and Table 12).

In addition to an over-presentation of the peptide, the mRNA expressionof the underlying gene was analyzed as well. mRNA data were obtained viaRNASeq analyses of normal tissues and cancer tissues (see Example 2). Anadditional source of normal tissue data was a database of publiclyavailable RNA expression data from around 3000 normal tissue samples(Lonsdale, 2013). Peptides which are derived from proteins that show ahighly expressed coding mRNA in cancer tissue, but a very low or absentone in vital healthy (normal) tissues, were included as preferred intothe present invention.

The present invention provides peptides that are useful in treatingcancers/tumors, preferably ovarian cancer that over- or exclusivelypresent the peptides of the invention. These peptides were shown by massspectrometry to be naturally presented by HLA molecules on primary humanovarian cancer samples.

Many of the source gene/proteins (also designated “full-length proteins”or “underlying proteins”) from which the peptides are derived were shownto be highly over-expressed in cancer compared with normaltissues—“normal tissues” in relation to this invention shall mean eitherhealthy ovaries or other normal tissues, demonstrating a high degree oftumor association of the source genes (see Example 2). Moreover, thepeptides themselves are strongly over-presented on tumor tissue—“tumortissue” in relation to this invention shall mean a sample from a patientsuffering from ovarian cancer, but not on normal tissues (see Example1).

HLA-bound peptides can be recognized by the immune system, specificallyT lymphocytes. T cells can destroy the cells presenting the recognizedHLA/peptide complex, e.g. ovarian cancer cells presenting the derivedpeptides.

The peptides of the present invention have been shown to be capable ofstimulating T cell responses and/or are over-presented and thus can beused for the production of antibodies and/or TCRs, such as soluble TCRs,according to the present invention (see Example 3, Example 4).Furthermore, the peptides when complexed with the respective MHC can beused for the production of antibodies and/or TCRs, in particular sTCRs,according to the present invention, as well. Respective methods are wellknown to the person of skill, and can be found in the respectiveliterature as well. Thus, the peptides of the present invention areuseful for generating an immune response in a patient by which tumorcells can be destroyed. An immune response in a patient can be inducedby direct administration of the described peptides or suitable precursorsubstances (e.g. elongated peptides, proteins, or nucleic acids encodingthese peptides) to the patient, ideally in combination with an agentenhancing the immunogenicity (i.e. an adjuvant). The immune responseoriginating from such a therapeutic vaccination can be expected to behighly specific against tumor cells because the target peptides of thepresent invention are not presented on normal tissues in comparable copynumbers, preventing the risk of undesired autoimmune reactions againstnormal cells in the patient.

The present description further relates to T-cell receptors (TCRs)comprising an alpha chain and a beta chain (“alpha/beta TCRs”). Alsoprovided are HAVCR1-001 peptides capable of binding to TCRs andantibodies when presented by an MHC molecule. The present descriptionalso relates to nucleic acids, vectors and host cells for expressingTCRs and peptides of the present description; and methods of using thesame.

The term “T-cell receptor” (abbreviated TCR) refers to a heterodimericmolecule comprising an alpha polypeptide chain (alpha chain) and a betapolypeptide chain (beta chain), wherein the heterodimeric receptor iscapable of binding to a peptide antigen presented by an HLA molecule.The term also includes so-called gamma/delta TCRs.

In one embodiment the description provides a method of producing a TCRas described herein, the method comprising culturing a host cell capableof expressing the TCR under conditions suitable to promote expression ofthe TCR.

The description in another aspect relates to methods according to thedescription, wherein the antigen is loaded onto class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellor artificial antigen-presenting cell by contacting a sufficient amountof the antigen with an antigen-presenting cell or the antigen is loadedonto class I or II MHC tetramers by tetramerizing the antigen/class I orII MHC complex monomers.

The alpha and beta chains of alpha/beta TCR's, and the gamma and deltachains of gamma/delta TCRs, are generally regarded as each having two“domains”, namely variable and constant domains. The variable domainconsists of a concatenation of variable region (V), and joining region(J). The variable domain may also include a leader region (L). Beta anddelta chains may also include a diversity region (D). The alpha and betaconstant domains may also include C-terminal transmembrane (TM) domainsthat anchor the alpha and beta chains to the cell membrane.

With respect to gamma/delta TCRs, the term “TCR gamma variable domain”as used herein refers to the concatenation of the TCR gamma V (TRGV)region without leader region (L), and the TCR gamma J (TRGJ) region, andthe term TCR gamma constant domain refers to the extracellular TRGCregion, or to a C-terminal truncated TRGC sequence. Likewise the term“TCR delta variable domain” refers to the concatenation of the TCR deltaV (TRDV) region without leader region (L) and the TCR delta D/J(TRDD/TRDJ) region, and the term “TCR delta constant domain” refers tothe extracellular TRDC region, or to a C-terminal truncated TRDCsequence.

TCRs of the present description preferably bind to an HAVCR1-001peptide-HLA molecule complex with a binding affinity (KD) of about 100μM or less, about 50 μM or less, about 25 μM or less, or about 10 μM orless. More preferred are high affinity TCRs having binding affinities ofabout 1 μM or less, about 100 nM or less, about 50 nM or less, about 25nM or less. Non-limiting examples of preferred binding affinity rangesfor TCRs of the present invention include about 1 nM to about 10 nM;about 10 nM to about 20 nM; about 20 nM to about 30 nM; about 30 nM toabout 40 nM; about 40 nM to about 50 nM; about 50 nM to about 60 nM;about 60 nM to about 70 nM; about 70 nM to about 80 nM; about 80 nM toabout 90 nM; and about 90 nM to about 100 nM.

As used herein in connect with TCRs of the present description,“specific binding” and grammatical variants thereof are used to mean aTCR having a binding affinity (KD) for an HAVCR1-001 peptide-HLAmolecule complex of 100 μM or less.

Alpha/beta heterodimeric TCRs of the present description may have anintroduced disulfide bond between their constant domains. Preferred TCRsof this type include those which have a TRAC constant domain sequenceand a TRBC1 or TRBC2 constant domain sequence except that Thr 48 of TRACand Ser 57 of TRBC1 or TRBC2 are replaced by cysteine residues, the saidcysteines forming a disulfide bond between the TRAC constant domainsequence and the TRBC1 or TRBC2 constant domain sequence of the TCR.

With or without the introduced inter-chain bond mentioned above,alpha/beta heterodimeric TCRs of the present description may have a TRACconstant domain sequence and a TRBC1 or TRBC2 constant domain sequence,and the TRAC constant domain sequence and the TRBC1 or TRBC2 constantdomain sequence of the TCR may be linked by the native disulfide bondbetween Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1 or TRBC2.

TCRs of the present description may comprise a detectable label selectedfrom the group consisting of a radionuclide, a fluorophore and biotin.TCRs of the present description may be conjugated to a therapeuticallyactive agent, such as a radionuclide, a chemotherapeutic agent, or atoxin.

In an embodiment, a TCR of the present description having at least onemutation in the alpha chain and/or having at least one mutation in thebeta chain has modified glycosylation compared to the unmutated TCR.

In an embodiment, a TCR comprising at least one mutation in the TCRalpha chain and/or TCR beta chain has a binding affinity for, and/or abinding half-life for, a HAVCR1-001 peptide-HLA molecule complex, whichis at least double that of a TCR comprising the unmutated TCR alphachain and/or unmutated TCR beta chain. Affinity-enhancement oftumor-specific TCRs, and its exploitation, relies on the existence of awindow for optimal TCR affinities. The existence of such a window isbased on observations that TCRs specific for HLA-A2-restricted pathogenshave KD values that are generally about 10-fold lower when compared toTCRs specific for HLA-A2-restricted tumor-associated self-antigens. Itis now known, although tumor antigens have the potential to beimmunogenic, because tumors arise from the individual's own cells onlymutated proteins or proteins with altered translational processing willbe seen as foreign by the immune system. Antigens that are upregulatedor overexpressed (so called self-antigens) will not necessarily induce afunctional immune response against the tumor: T-cells expressing TCRsthat are highly reactive to these antigens will have been negativelyselected within the thymus in a process known as central tolerance,meaning that only T-cells with low-affinity TCRs for self-antigensremain. Therefore, affinity of TCRs or variants of the presentdescription to HAVCR1-001 can be enhanced by methods well known in theart.

The present description further relates to a method of identifying andisolating a TCR according to the present description, said methodcomprising incubating PBMCs from HLA-A*02-negative healthy donors withA2/HAVCR1-001 monomers, incubating the PBMCs with tetramer-phycoerythrin(PE) and isolating the high avidity T-cells by fluorescence activatedcell sorting (FACS)-Calibur analysis.

The present description further relates to a method of identifying andisolating a TCR according to the present description, said methodcomprising obtaining a transgenic mouse with the entire human TCRαβ geneloci (1.1 and 0.7 Mb), whose T-cells express a diverse human TCRrepertoire that compensates for mouse TCR deficiency, immunizing themouse with HAVCR1-001, incubating PBMCs obtained from the transgenicmice with tetramer-phycoerythrin (PE), and isolating the high avidityT-cells by fluorescence activated cell sorting (FACS)-Calibur analysis.

In one aspect, to obtain T-cells expressing TCRs of the presentdescription, nucleic acids encoding TCR-alpha and/or TCR-beta chains ofthe present description are cloned into expression vectors, such asgamma retrovirus or lentivirus. The recombinant viruses are generatedand then tested for functionality, such as antigen specificity andfunctional avidity. An aliquot of the final product is then used totransduce the target T-cell population (generally purified from patientPBMCs), which is expanded before infusion into the patient.

In another aspect, to obtain T-cells expressing TCRs of the presentdescription, TCR RNAs are synthesized by techniques known in the art,e.g., in vitro transcription systems. The in vitro-synthesized TCR RNAsare then introduced into primary CD8+ T-cells obtained from healthydonors by electroporation to re-express tumor specific TCR-alpha and/orTCR-beta chains.

To increase the expression, nucleic acids encoding TCRs of the presentdescription may be operably linked to strong promoters, such asretroviral long terminal repeats (LTRs), cytomegalovirus (CMV), murinestem cell virus (MSCV) U3, phosphoglycerate kinase (PGK), β-actin,ubiquitin, and a simian virus 40 (SV40)/CD43 composite promoter,elongation factor (EF)-1a and the spleen focus-forming virus (SFFV)promoter. In a preferred embodiment, the promoter is heterologous to thenucleic acid being expressed.

In addition to strong promoters, TCR expression cassettes of the presentdescription may contain additional elements that can enhance transgeneexpression, including a central polypurine tract (cPPT), which promotesthe nuclear translocation of lentiviral constructs (Follenzi et al.,2000), and the woodchuck hepatitis virus posttranscriptional regulatoryelement (wPRE), which increases the level of transgene expression byincreasing RNA stability (Zufferey et al., 1999).

The alpha and beta chains of a TCR of the present invention may beencoded by nucleic acids located in separate vectors, or may be encodedby polynucleotides located in the same vector.

Achieving high-level TCR surface expression requires that both theTCR-alpha and TCR-beta chains of the introduced TCR be transcribed athigh levels. To do so, the TCR-alpha and TCR-beta chains of the presentdescription may be cloned into bi-cistronic constructs in a singlevector, which has been shown to be capable of over-coming this obstacle.The use of a viral intraribosomal entry site (IRES) between theTCR-alpha and TCR-beta chains results in the coordinated expression ofboth chains, because the TCR-alpha and TCR-beta chains are generatedfrom a single transcript that is broken into two proteins duringtranslation, ensuring that an equal molar ratio of TCR-alpha andTCR-beta chains are produced. (Schmitt et al. 2009).

Nucleic acids encoding TCRs of the present description may be codonoptimized to increase expression from a host cell. Redundancy in thegenetic code allows some amino acids to be encoded by more than onecodon, but certain codons are less “optimal” than others because of therelative availability of matching tRNAs as well as other factors(Gustafsson et al., 2004). Modifying the TCR-alpha and TCR-beta genesequences such that each amino acid is encoded by the optimal codon formammalian gene expression, as well as eliminating mRNA instabilitymotifs or cryptic splice sites, has been shown to significantly enhanceTCR-alpha and TCR-beta gene expression (Scholten et al., 2006).

Furthermore, mispairing between the introduced and endogenous TCR chainsmay result in the acquisition of specificities that pose a significantrisk for autoimmunity. For example, the formation of mixed TCR dimersmay reduce the number of CD3 molecules available to form properly pairedTCR complexes, and therefore can significantly decrease the functionalavidity of the cells expressing the introduced TCR (Kuball et al.,2007).

To reduce mispairing, the C-terminus domain of the introduced TCR chainsof the present description may be modified in order to promoteinterchain affinity, while de-creasing the ability of the introducedchains to pair with the endogenous TCR. These strategies may includereplacing the human TCR-alpha and TCR-beta C-terminus domains with theirmurine counterparts (murinized C-terminus domain); generating a secondinterchain disulfide bond in the C-terminus domain by introducing asecond cysteine residue into both the TCR-alpha and TCR-beta chains ofthe introduced TCR (cysteine modification); swapping interactingresidues in the TCR-alpha and TCR-beta chain C-terminus domains(“knob-in-hole”); and fusing the variable domains of the TCR-alpha andTCR-beta chains directly to CD3ζ (CD3ζ fusion). (Schmitt et al. 2009).

In an embodiment, a host cell is engineered to express a TCR of thepresent description. In preferred embodiments, the host cell is a humanT-cell or T-cell progenitor. In some embodiments the T-cell or T-cellprogenitor is obtained from a cancer patient. In other embodiments theT-cell or T-cell progenitor is obtained from a healthy donor. Host cellsof the present description can be allogeneic or autologous with respectto a patient to be treated. In one embodiment, the host is a gamma/deltaT-cell transformed to express an alpha/beta TCR.

A “pharmaceutical composition” is a composition suitable foradministration to a human being in a medical setting. Preferably, apharmaceutical composition is sterile and produced according to GMPguidelines.

The pharmaceutical compositions comprise the peptides either in the freeform or in the form of a pharmaceutically acceptable salt (see alsoabove). As used herein, “a pharmaceutically acceptable salt” refers to aderivative of the disclosed peptides wherein the peptide is modified bymaking acid or base salts of the agent. For example, acid salts areprepared from the free base (typically wherein the neutral form of thedrug has a neutral —NH2 group) involving reaction with a suitable acid.Suitable acids for preparing acid salts include both organic acids,e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonicacid, salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acidphosphoric acid and the like. Conversely, preparation of basic salts ofacid moieties which may be present on a peptide are prepared using apharmaceutically acceptable base such as sodium hydroxide, potassiumhydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or thelike.

In an especially preferred embodiment, the pharmaceutical compositionscomprise the peptides as salts of acetic acid (acetates), trifluoroacetates or hydrochloric acid (chlorides).

Preferably, the medicament of the present invention is animmunotherapeutics such as a vaccine. It may be administered directlyinto the patient, into the affected organ or systemically i.d., i.m.,s.c., i.p. and i.v., or applied ex vivo to cells derived from thepatient or a human cell line which are subsequently administered to thepatient, or used in vitro to select a subpopulation of immune cellsderived from the patient, which are then re-administered to the patient.If the nucleic acid is administered to cells in vitro, it may be usefulfor the cells to be transfected so as to co-express immune-stimulatingcytokines, such as interleukin-2. The peptide may be substantially pure,or combined with an immune-stimulating adjuvant (see below) or used incombination with immune-stimulatory cytokines, or be administered with asuitable delivery system, for example liposomes. The peptide may also beconjugated to a suitable carrier such as keyhole limpet haemocyanin(KLH) or mannan (see WO 95/18145 and (Longenecker et al., 1993)). Thepeptide may also be tagged, may be a fusion protein, or may be a hybridmolecule. The peptides whose sequence is given in the present inventionare expected to stimulate CD4 or CD8 T cells. However, stimulation ofCD8 T cells is more efficient in the presence of help provided by CD4T-helper cells. Thus, for MHC Class I epitopes that stimulate CD8 Tcells the fusion partner or sections of a hybrid molecule suitablyprovide epitopes which stimulate CD4-positive T cells. CD4- andCD8-stimulating epitopes are well known in the art and include thoseidentified in the present invention.

In one aspect, the vaccine comprises at least one peptide having theamino acid sequence set forth SEQ ID No. 1 to SEQ ID No. 640, and atleast one additional peptide, preferably two to 50, more preferably twoto 25, even more preferably two to 20 and most preferably two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen or eighteen peptides. Thepeptide(s) may be derived from one or more specific TAAs and may bind toMHC class I molecules.

A further aspect of the invention provides a nucleic acid (for example apolynucleotide) encoding a peptide or peptide variant of the invention.The polynucleotide may be, for example, DNA, cDNA, PNA, RNA orcombinations thereof, either single- and/or double-stranded, or nativeor stabilized forms of polynucleotides, such as, for example,polynucleotides with a phosphorothioate backbone and it may or may notcontain introns so long as it codes for the peptide. Of course, onlypeptides that contain naturally occurring amino acid residues joined bynaturally occurring peptide bonds are encodable by a polynucleotide. Astill further aspect of the invention provides an expression vectorcapable of expressing a polypeptide according to the invention.

A variety of methods have been developed to link polynucleotides,especially DNA, to vectors for example via complementary cohesivetermini. For instance, complementary homopolymer tracts can be added tothe DNA segment to be inserted to the vector DNA. The vector and DNAsegment are then joined by hydrogen bonding between the complementaryhomopolymeric tails to form recombinant DNA molecules.

Synthetic linkers containing one or more restriction sites provide analternative method of joining the DNA segment to vectors. Syntheticlinkers containing a variety of restriction endonuclease sites arecommercially available from a number of sources including InternationalBiotechnologies Inc. New Haven, Conn., USA.

A desirable method of modifying the DNA encoding the polypeptide of theinvention employs the polymerase chain reaction as disclosed by Saiki RK, et al. (Saiki et al., 1988). This method may be used for introducingthe DNA into a suitable vector, for example by engineering in suitablerestriction sites, or it may be used to modify the DNA in other usefulways as is known in the art. If viral vectors are used, pox- oradenovirus vectors are preferred.

The DNA (or in the case of retroviral vectors, RNA) may then beexpressed in a suitable host to produce a polypeptide comprising thepeptide or variant of the invention. Thus, the DNA encoding the peptideor variant of the invention may be used in accordance with knowntechniques, appropriately modified in view of the teachings containedherein, to construct an expression vector, which is then used totransform an appropriate host cell for the expression and production ofthe polypeptide of the invention. Such techniques include thosedisclosed, for example, in U.S. Pat. Nos. 4,440,859, 4,530,901,4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 4,757,006,4,766,075, and 4,810,648.

The DNA (or in the case of retroviral vectors, RNA) encoding thepolypeptide constituting the compound of the invention may be joined toa wide variety of other DNA sequences for introduction into anappropriate host. The companion DNA will depend upon the nature of thehost, the manner of the introduction of the DNA into the host, andwhether episomal maintenance or integration is desired.

Generally, the DNA is inserted into an expression vector, such as aplasmid, in proper orientation and correct reading frame for expression.If necessary, the DNA may be linked to the appropriate transcriptionaland translational regulatory control nucleotide sequences recognized bythe desired host, although such controls are generally available in theexpression vector. The vector is then introduced into the host throughstandard techniques. Generally, not all of the hosts will be transformedby the vector. Therefore, it will be necessary to select for transformedhost cells. One selection technique involves incorporating into theexpression vector a DNA sequence, with any necessary control elements,that codes for a selectable trait in the transformed cell, such asantibiotic resistance.

Alternatively, the gene for such selectable trait can be on anothervector, which is used to co-transform the desired host cell.

Host cells that have been transformed by the recombinant DNA of theinvention are then cultured for a sufficient time and under appropriateconditions known to those skilled in the art in view of the teachingsdisclosed herein to permit the expression of the polypeptide, which canthen be recovered.

Many expression systems are known, including bacteria (for example E.coli and Bacillus subtilis), yeasts (for example Saccharomycescerevisiae), filamentous fungi (for example Aspergillus spec.), plantcells, animal cells and insect cells. Preferably, the system can bemammalian cells such as CHO cells available from the ATCC Cell BiologyCollection.

A typical mammalian cell vector plasmid for constitutive expressioncomprises the CMV or SV40 promoter with a suitable poly A tail and aresistance marker, such as neomycin. One example is pSVL available fromPharmacia, Piscataway, N.J., USA. An example of an inducible mammalianexpression vector is pMSG, also available from Pharmacia. Useful yeastplasmid vectors are pRS403-406 and pRS413-416 and are generallyavailable from Stratagene Cloning Systems, La Jolla, Calif. 92037, USA.Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integratingplasmids (Ylps) and incorporate the yeast selectable markers HIS3, TRP1,LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps).CMV promoter-based vectors (for example from Sigma-Aldrich) providetransient or stable expression, cytoplasmic expression or secretion, andN-terminal or C-terminal tagging in various combinations of FLAG,3×FLAG, c-myc or MAT. These fusion proteins allow for detection,purification and analysis of recombinant protein. Dual-tagged fusionsprovide flexibility in detection.

The strong human cytomegalovirus (CMV) promoter regulatory region drivesconstitutive protein expression levels as high as 1 mg/L in COS cells.For less potent cell lines, protein levels are typically ˜0.1 mg/L. Thepresence of the SV40 replication origin will result in high levels ofDNA replication in SV40 replication permissive COS cells. CMV vectors,for example, can contain the pMB1 (derivative of pBR322) origin forreplication in bacterial cells, the b-lactamase gene for ampicillinresistance selection in bacteria, hGH polyA, and the f1 origin. Vectorscontaining the pre-pro-trypsin leader (PPT) sequence can direct thesecretion of FLAG fusion proteins into the culture medium forpurification using ANTI-FLAG antibodies, resins, and plates. Othervectors and expression systems are well known in the art for use with avariety of host cells.

In another embodiment two or more peptides or peptide variants of theinvention are encoded and thus expressed in a successive order (similarto “beads on a string” constructs). In doing so, the peptides or peptidevariants may be linked or fused together by stretches of linker aminoacids, such as for example LLLLLL, or may be linked without anyadditional peptide(s) between them. These constructs can also be usedfor cancer therapy, and may induce immune responses both involving MHC Iand MHC II.

The present invention also relates to a host cell transformed with apolynucleotide vector construct of the present invention. The host cellcan be either prokaryotic or eukaryotic. Bacterial cells may bepreferred prokaryotic host cells in some circumstances and typically area strain of E. coli such as, for example, the E. coli strains DH5available from Bethesda Research Laboratories Inc., Bethesda, Md., USA,and RR1 available from the American Type Culture Collection (ATCC) ofRockville, Md., USA (No ATCC 31343).

Preferred eukaryotic host cells include yeast, insect and mammaliancells, preferably vertebrate cells such as those from a mouse, rat,monkey or human fibroblastic and colon cell lines. Yeast host cellsinclude YPH499, YPH500 and YPH501, which are generally available fromStratagene Cloning Systems, La Jolla, Calif. 92037, USA. Preferredmammalian host cells include Chinese hamster ovary (CHO) cells availablefrom the ATCC as CCL61, NIH Swiss mouse embryo cells NIH/3T3 availablefrom the ATCC as CRL 1658, monkey kidney-derived COS-1 cells availablefrom the ATCC as CRL 1650 and 293 cells which are human embryonic kidneycells. Preferred insect cells are Sf9 cells which can be transfectedwith baculovirus expression vectors. An overview regarding the choice ofsuitable host cells for expression can be found in, for example, thetextbook of Paulina Balbás and Argelia Lorence “Methods in MolecularBiology Recombinant Gene Expression, Reviews and Protocols,” Part One,Second Edition, ISBN 978-1-58829-262-9, and other literature known tothe person of skill.

Transformation of appropriate cell hosts with a DNA construct of thepresent invention is accomplished by well-known methods that typicallydepend on the type of vector used. With regard to transformation ofprokaryotic host cells, see, for example, Cohen et al. (Cohen et al.,1972) and (Green and Sambrook, 2012). Transformation of yeast cells isdescribed in Sherman et al. (Sherman et al., 1986). The method of Beggs(Beggs, 1978) is also useful. With regard to vertebrate cells, reagentsuseful in transfecting such cells, for example calcium phosphate andDEAE-dextran or liposome formulations, are available from StratageneCloning Systems, or Life Technologies Inc., Gaithersburg, Md. 20877,USA. Electroporation is also useful for transforming and/or transfectingcells and is well known in the art for transforming yeast cell,bacterial cells, insect cells and vertebrate cells.

Successfully transformed cells, i.e. cells that contain a DNA constructof the present invention, can be identified by well-known techniquessuch as PCR. Alternatively, the presence of the protein in thesupernatant can be detected using antibodies.

It will be appreciated that certain host cells of the invention areuseful in the preparation of the peptides of the invention, for examplebacterial, yeast and insect cells. However, other host cells may beuseful in certain therapeutic methods. For example, antigen-presentingcells, such as dendritic cells, may usefully be used to express thepeptides of the invention such that they may be loaded into appropriateMHC molecules. Thus, the current invention provides a host cellcomprising a nucleic acid or an expression vector according to theinvention.

In a preferred embodiment the host cell is an antigen presenting cell,in particular a dendritic cell or antigen presenting cell. APCs loadedwith a recombinant fusion protein containing prostatic acid phosphatase(PAP) were approved by the U.S. Food and Drug Administration (FDA) onApr. 29, 2010, to treat asymptomatic or minimally symptomatic metastaticHRPC (Sipuleucel-T) (Rini et al., 2006; Small et al., 2006).

A further aspect of the invention provides a method of producing apeptide or its variant, the method comprising culturing a host cell andisolating the peptide from the host cell or its culture medium.

In another embodiment the peptide, the nucleic acid or the expressionvector of the invention are used in medicine. For example, the peptideor its variant may be prepared for intravenous (i.v.) injection,sub-cutaneous (s.c.) injection, intradermal (i.d.) injection,intraperitoneal (i.p.) injection, intramuscular (i.m.) injection.Preferred methods of peptide injection include s.c., i.d., i.p., i.m.,and i.v. Preferred methods of DNA injection include i.d., i.m., s.c.,i.p. and i.v. Doses of e.g. between 50 μg and 1.5 mg, preferably 125 μgto 500 μg, of peptide or DNA may be given and will depend on therespective peptide or DNA. Dosages of this range were successfully usedin previous trials (Walter et al., 2012).

The polynucleotide used for active vaccination may be substantiallypure, or contained in a suitable vector or delivery system. The nucleicacid may be DNA, cDNA, PNA, RNA or a combination thereof. Methods fordesigning and introducing such a nucleic acid are well known in the art.An overview is provided by e.g. Teufel et al. (Teufel et al., 2005).

Polynucleotide vaccines are easy to prepare, but the mode of action ofthese vectors in inducing an immune response is not fully understood.Suitable vectors and delivery systems include viral DNA and/or RNA, suchas systems based on adenovirus, vaccinia virus, retroviruses, herpesvirus, adeno-associated virus or hybrids containing elements of morethan one virus. Non-viral delivery systems include cationic lipids andcationic polymers and are well known in the art of DNA delivery.Physical delivery, such as via a “gene-gun” may also be used. Thepeptide or peptides encoded by the nucleic acid may be a fusion protein,for example with an epitope that stimulates T cells for the respectiveopposite CDR as noted above.

The medicament of the invention may also include one or more adjuvants.Adjuvants are substances that non-specifically enhance or potentiate theimmune response (e.g., immune responses mediated by CD8-positive T cellsand helper-T (TH) cells to an antigen, and would thus be considereduseful in the medicament of the present invention. Suitable adjuvantsinclude, but are not limited to, 1018 ISS, aluminum salts, AMPLIVAX®,AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, flagellin or TLR5 ligandsderived from flagellin, FLT3 ligand, GM-CSF, IC30, IC31, Imiquimod(ALDARA®), resiquimod, ImuFact IMP321, Interleukins as IL-2, IL-13,IL-21, Interferon-alpha or -beta, or pegylated derivatives thereof, ISPatch, ISS, ISCOMATRIX, ISCOMs, JuvImmune®, LipoVac, MALP2, MF59,monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, MontanideISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions,OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® vector system,poly(lactid co-glycolid) [PLG]-based and dextran microparticles,talactoferrin SRL172, Virosomes and other Virus-like particles, YF-17D,VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, which isderived from saponin, mycobacterial extracts and synthetic bacterialcell wall mimics, and other proprietary adjuvants such as Ribi's Detox,Quil, or Superfos. Adjuvants such as Freund's or GM-CSF are preferred.Several immunological adjuvants (e.g., MF59) specific for dendriticcells and their preparation have been described previously (Allison andKrummel, 1995). Also cytokines may be used. Several cytokines have beendirectly linked to influencing dendritic cell migration to lymphoidtissues (e.g., TNF-), accelerating the maturation of dendritic cellsinto efficient antigen-presenting cells for T-lymphocytes (e.g., GM-CSF,IL-1 and IL-4) (U.S. Pat. No. 5,849,589, specifically incorporatedherein by reference in its entirety) and acting as immunoadjuvants(e.g., IL-12, IL-15, IL-23, IL-7, IFN-alpha. IFN-beta) (Gabrilovich etal., 1996).

CpG immunostimulatory oligonucleotides have also been reported toenhance the effects of adjuvants in a vaccine setting. Without beingbound by theory, CpG oligonucleotides act by activating the innate(non-adaptive) immune system via Toll-like receptors (TLR), mainly TLR9.CpG triggered TLR9 activation enhances antigen-specific humoral andcellular responses to a wide variety of antigens, including peptide orprotein antigens, live or killed viruses, dendritic cell vaccines,autologous cellular vaccines and polysaccharide conjugates in bothprophylactic and therapeutic vaccines. More importantly it enhancesdendritic cell maturation and differentiation, resulting in enhancedactivation of TH1 cells and strong cytotoxic T-lymphocyte (CTL)generation, even in the absence of CD4 T cell help. The TH1 bias inducedby TLR9 stimulation is maintained even in the presence of vaccineadjuvants such as alum or incomplete Freund's adjuvant (IFA) thatnormally promote a TH2 bias. CpG oligonucleotides show even greateradjuvant activity when formulated or co-administered with otheradjuvants or in formulations such as microparticles, nanoparticles,lipid emulsions or similar formulations, which are especially necessaryfor inducing a strong response when the antigen is relatively weak. Theyalso accelerate the immune response and enable the antigen doses to bereduced by approximately two orders of magnitude, with comparableantibody responses to the full-dose vaccine without CpG in someexperiments (Krieg, 2006). U.S. Pat. No. 6,406,705 B1 describes thecombined use of CpG oligonucleotides, non-nucleic acid adjuvants and anantigen to induce an antigen-specific immune response. A CpG TLR9antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen(Berlin, Germany) which is a preferred component of the pharmaceuticalcomposition of the present invention. Other TLR binding molecules suchas RNA binding TLR 7, TLR 8 and/or TLR 9 may also be used.

Other examples for useful adjuvants include, but are not limited tochemically modified CpGs (e.g. CpR, Idera), dsRNA analogues such asPoly(I:C) and derivates thereof (e.g. AmpliGen®, Hiltonol®, poly-(ICLC),poly(IC-R), poly(I:C12U), non-CpG bacterial DNA or RNA as well asimmunoactive small molecules and antibodies such as cyclophosphamide,sunitinib, Bevacizumab®, celebrex, NCX-4016, sildenafil, tadalafil,vardenafil, sorafenib, temozolomide, temsirolimus, XL-999, CP-547632,pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other antibodiestargeting key structures of the immune system (e.g. anti-CD40,anti-TGFbeta, anti-TNFalpha receptor) and SC58175, which may acttherapeutically and/or as an adjuvant. The amounts and concentrations ofadjuvants and additives useful in the context of the present inventioncan readily be determined by the skilled artisan without undueexperimentation.

Preferred adjuvants are anti-CD40, imiquimod, resiquimod, GM-CSF,cyclophosphamide, sunitinib, bevacizumab, interferon-alpha, CpGoligonucleotides and derivates, poly-(I:C) and derivates, RNA,sildenafil, and particulate formulations with PLG or virosomes.

In a preferred embodiment, the pharmaceutical composition according tothe invention the adjuvant is selected from the group consisting ofcolony-stimulating factors, such as Granulocyte Macrophage ColonyStimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimod,resiquimod, and interferon-alpha.

In a preferred embodiment, the pharmaceutical composition according tothe invention the adjuvant is selected from the group consisting ofcolony-stimulating factors, such as Granulocyte Macrophage ColonyStimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimodand resiquimod. In a preferred embodiment of the pharmaceuticalcomposition according to the invention, the adjuvant iscyclophosphamide, imiquimod or resiquimod. Even more preferred adjuvantsare Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, MontanideISA-51, poly-ICLC (Hiltonol®) and anti-CD40 mAB, or combinationsthereof.

This composition is used for parenteral administration, such assubcutaneous, intradermal, intramuscular or oral administration. Forthis, the peptides and optionally other molecules are dissolved orsuspended in a pharmaceutically acceptable, preferably aqueous carrier.In addition, the composition can contain excipients, such as buffers,binding agents, blasting agents, diluents, flavors, lubricants, etc. Thepeptides can also be administered together with immune stimulatingsubstances, such as cytokines. An extensive listing of excipients thatcan be used in such a composition, can be, for example, taken from A.Kibbe, Handbook of Pharmaceutical Excipients (Kibbe, 2000). Thecomposition can be used for a prevention, prophylaxis and/or therapy ofadenomatous or cancerous diseases. Exemplary formulations can be foundin, for example, EP2112253.

It is important to realize that the immune response triggered by thevaccine according to the invention attacks the cancer in differentcell-stages and different stages of development. Furthermore, differentcancer associated signaling pathways are attacked. This is an advantageover vaccines that address only one or few targets, which may cause thetumor to easily adapt to the attack (tumor escape). Furthermore, not allindividual tumors express the same pattern of antigens. Therefore, acombination of several tumor-associated peptides ensures that everysingle tumor bears at least some of the targets. The composition isdesigned in such a way that each tumor is expected to express several ofthe antigens and cover several independent pathways necessary for tumorgrowth and maintenance. Thus, the vaccine can easily be used“off-the-shelf” for a larger patient population. This means that apre-selection of patients to be treated with the vaccine can berestricted to HLA typing, does not require any additional biomarkerassessments for antigen expression, but it is still ensured that severaltargets are simultaneously attacked by the induced immune response,which is important for efficacy (Banchereau et al., 2001; Walter et al.,2012).

As used herein, the term “scaffold” refers to a molecule thatspecifically binds to an (e.g. antigenic) determinant. In oneembodiment, a scaffold is able to direct the entity to which it isattached (e.g. a (second) antigen binding moiety) to a target site, forexample to a specific type of tumor cell or tumor stroma bearing theantigenic determinant (e.g. the complex of a peptide with MHC, accordingto the application at hand). In another embodiment a scaffold is able toactivate signaling through its target antigen, for example a T cellreceptor complex antigen. Scaffolds include but are not limited toantibodies and fragments thereof, antigen binding domains of anantibody, comprising an antibody heavy chain variable region and anantibody light chain variable region, binding proteins comprising atleast one Ankyrin repeat motif and single domain antigen binding (SDAB)molecules, aptamers, (soluble) TCRs and (modified) cells such asallogenic or autologous T cells. To assess whether a molecule is ascaffold binding to a target, binding assays can be performed.

“Specific” binding means that the scaffold binds the peptide-MHC-complexof interest better than other naturally occurring peptide-MHC-complexes,to an extent that a scaffold armed with an active molecule that is ableto kill a cell bearing the specific target is not able to kill anothercell without the specific target but presenting other peptide-MHCcomplex(es). Binding to other peptide-MHC complexes is irrelevant if thepeptide of the cross-reactive peptide-MHC is not naturally occurring,i.e. not derived from the human HLA-peptidome. Tests to assess targetcell killing are well known in the art. They should be performed usingtarget cells (primary cells or cell lines) with unaltered peptide-MHCpresentation, or cells loaded with peptides such that naturallyoccurring peptide-MHC levels are reached.

Each scaffold can comprise a labelling which provides that the boundscaffold can be detected by determining the presence or absence of asignal provided by the label. For example, the scaffold can be labelledwith a fluorescent dye or any other applicable cellular marker molecule.Such marker molecules are well known in the art. For example, afluorescence-labelling, for example provided by a fluorescence dye, canprovide a visualization of the bound aptamer by fluorescence or laserscanning microscopy or flow cytometry.

Each scaffold can be conjugated with a second active molecule such asfor example IL-21, anti-CD3, anti-CD28.

For further information on polypeptide scaffolds see for example thebackground section of WO 2014/071978A1 and the references cited therein.

The present invention further relates to aptamers. Aptamers (see forexample WO 2014/191359 and the literature as cited therein) are shortsingle-stranded nucleic acid molecules, which can fold into definedthree-dimensional structures and recognize specific target structures.They have appeared to be suitable alternatives for developing targetedtherapies. Aptamers have been shown to selectively bind to a variety ofcomplex targets with high affinity and specificity.

Aptamers recognizing cell surface located molecules have been identifiedwithin the past decade and provide means for developing diagnostic andtherapeutic approaches. Since aptamers have been shown to possess almostno toxicity and immunogenicity they are promising candidates forbiomedical applications. Indeed, aptamers, for example prostate-specificmembrane-antigen recognizing aptamers, have been successfully employedfor targeted therapies and shown to be functional in xenograft in vivomodels. Furthermore, aptamers recognizing specific tumor cell lines havebeen identified.

DNA aptamers can be selected to reveal broad-spectrum recognitionproperties for various cancer cells, and particularly those derived fromsolid tumors, while non-tumorigenic and primary healthy cells are notrecognized. If the identified aptamers recognize not only a specifictumor sub-type but rather interact with a series of tumors, this rendersthe aptamers applicable as so-called broad-spectrum diagnostics andtherapeutics.

Further, investigation of cell-binding behavior with flow cytometryshowed that the aptamers revealed very good apparent affinities that arewithin the nanomolar range.

Aptamers are useful for diagnostic and therapeutic purposes. Further, itcould be shown that some of the aptamers are taken up by tumor cells andthus can function as molecular vehicles for the targeted delivery ofanti-cancer agents such as siRNA into tumor cells.

Aptamers can be selected against complex targets such as cells andtissues and complexes of the peptides comprising, preferably consistingof, a sequence according to any of SEQ ID NO 1 to SEQ ID NO 640,according to the invention at hand with the MHC molecule, using thecell-SELEX (Systematic Evolution of Ligands by Exponential enrichment)technique.

The peptides of the present invention can be used to generate anddevelop specific antibodies against MHC/peptide complexes. These can beused for therapy, targeting toxins or radioactive substances to thediseased tissue. Another use of these antibodies can be targetingradionuclides to the diseased tissue for imaging purposes such as PET.This use can help to detect small metastases or to determine the sizeand precise localization of diseased tissues.

Therefore, it is a further aspect of the invention to provide a methodfor producing a recombinant antibody specifically binding to a humanmajor histocompatibility complex (MHC) class I or II being complexedwith a HLA-restricted antigen, the method comprising: immunizing agenetically engineered non-human mammal comprising cells expressing saidhuman major histocompatibility complex (MHC) class I or II with asoluble form of a MHC class I or II molecule being complexed with saidHLA-restricted antigen; isolating mRNA molecules from antibody producingcells of said non-human mammal; producing a phage display librarydisplaying protein molecules encoded by said mRNA molecules; andisolating at least one phage from said phage display library, said atleast one phage displaying said antibody specifically binding to saidhuman major histocompatibility complex (MHC) class I or II beingcomplexed with said HLA-restricted antigen.

It is a further aspect of the invention to provide an antibody thatspecifically binds to a human major histocompatibility complex (MHC)class I or II being complexed with a HLA-restricted antigen, wherein theantibody preferably is a polyclonal antibody, monoclonal antibody,bi-specific antibody and/or a chimeric antibody.

Respective methods for producing such antibodies and single chain classI major histocompatibility complexes, as well as other tools for theproduction of these antibodies are disclosed in WO 03/068201, WO2004/084798, WO 01/72768, WO 03/070752, and in publications (Cohen etal., 2003a; Cohen et al., 2003b; Denkberg et al., 2003), which for thepurposes of the present invention are all explicitly incorporated byreference in their entireties.

Preferably, the antibody is binding with a binding affinity of below 20nanomolar, preferably of below 10 nanomolar, to the complex, which isalso regarded as “specific” in the context of the present invention.

The present invention relates to a peptide comprising a sequence that isselected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 640, ora variant thereof which is at least 88% homologous (preferablyidentical) to SEQ ID NO: 1 to SEQ ID NO: 640 or a variant thereof thatinduces T cells cross-reacting with said peptide, wherein said peptideis not the underlying full-length polypeptide.

The present invention further relates to a peptide comprising a sequencethat is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO:640 or a variant thereof which is at least 88% homologous (preferablyidentical) to SEQ ID NO: 1 to SEQ ID NO: 640, wherein said peptide orvariant has an overall length of between 8 and 100, preferably between 8and 30, and most preferred between 8 and 14 amino acids.

The present invention further relates to the peptides according to theinvention that have the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class-I or -II.

The present invention further relates to the peptides according to theinvention wherein the peptide consists or consists essentially of anamino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 640.

The present invention further relates to the peptides according to theinvention, wherein the peptide is (chemically) modified and/or includesnon-peptide bonds.

The present invention further relates to the peptides according to theinvention, wherein the peptide is part of a fusion protein, inparticular comprising N-terminal amino acids of the HLA-DRantigen-associated invariant chain (li), or wherein the peptide is fusedto (or into) an antibody, such as, for example, an antibody that isspecific for dendritic cells.

The present invention further relates to a nucleic acid, encoding thepeptides according to the invention, provided that the peptide is notthe complete (full) human protein.

The present invention further relates to the nucleic acid according tothe invention that is DNA, cDNA, PNA, RNA or combinations thereof.

The present invention further relates to an expression vector capable ofexpressing a nucleic acid according to the present invention.

The present invention further relates to a peptide according to thepresent invention, a nucleic acid according to the present invention oran expression vector according to the present invention for use inmedicine, in particular in the treatment of ovarian cancer.

The present invention further relates to a host cell comprising anucleic acid according to the invention or an expression vectoraccording to the invention.

The present invention further relates to the host cell according to thepresent invention that is an antigen presenting cell, and preferably adendritic cell.

The present invention further relates to a method of producing a peptideaccording to the present invention, said method comprising culturing thehost cell according to the present invention, and isolating the peptidefrom said host cell or its culture medium.

The present invention further relates to the method according to thepresent invention, wherein the antigen is loaded onto class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellby contacting a sufficient amount of the antigen with anantigen-presenting cell.

The present invention further relates to the method according to theinvention, wherein the antigen-presenting cell comprises an expressionvector capable of expressing said peptide containing SEQ ID NO: 1 to SEQID NO: 640 or said variant amino acid sequence.

The present invention further relates to activated T cells, produced bythe method according to the present invention, wherein said T cellsselectively recognizes a cell which aberrantly expresses a polypeptidecomprising an amino acid sequence according to the present invention.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence according to the present invention,the method comprising administering to the patient an effective numberof T cells as according to the present invention.

The present invention further relates to the use of any peptidedescribed, a nucleic acid according to the present invention, anexpression vector according to the present invention, a cell accordingto the present invention, or an activated cytotoxic T lymphocyteaccording to the present invention as a medicament or in the manufactureof a medicament. The present invention further relates to a useaccording to the present invention, wherein the medicament is activeagainst cancer.

The present invention further relates to a use according to theinvention, wherein the medicament is a vaccine. The present inventionfurther relates to a use according to the invention, wherein themedicament is active against cancer.

The present invention further relates to a use according to theinvention, wherein said cancer cells are ovarian cancer cells or othersolid or hematological tumor cells such as non-small cell lung cancer,small cell lung cancer, kidney cancer, brain cancer, colon or rectumcancer, stomach cancer, liver cancer, pancreatic cancer, prostatecancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma,esophageal cancer, urinary bladder cancer, uterine cancer, gallbladdercancer, bile duct cancer.

The present invention further relates to particular marker proteins andbiomarkers based on the peptides according to the present invention,herein called “targets” that can be used in the diagnosis and/orprognosis of ovarian cancer. The present invention also relates to theuse of these novel targets for cancer treatment.

The term “antibody” or “antibodies” is used herein in a broad sense andincludes both polyclonal and monoclonal antibodies. In addition tointact or “full” immunoglobulin molecules, also included in the term“antibodies” are fragments (e.g. CDRs, Fv, Fab and Fc fragments) orpolymers of those immunoglobulin molecules and humanized versions ofimmunoglobulin molecules, as long as they exhibit any of the desiredproperties (e.g., specific binding of a ovarian cancer marker(poly)peptide, delivery of a toxin to a ovarian cancer cell expressing acancer marker gene at an increased level, and/or inhibiting the activityof a ovarian cancer marker polypeptide) according to the invention.

Whenever possible, the antibodies of the invention may be purchased fromcommercial sources. The antibodies of the invention may also begenerated using well-known methods. The skilled artisan will understandthat either full length ovarian cancer marker polypeptides or fragmentsthereof may be used to generate the antibodies of the invention. Apolypeptide to be used for generating an antibody of the invention maybe partially or fully purified from a natural source, or may be producedusing recombinant DNA techniques.

For example, a cDNA encoding a peptide according to the presentinvention, such as a peptide according to SEQ ID NO: 1 to SEQ ID NO: 640polypeptide, or a variant or fragment thereof, can be expressed inprokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast,insect, or mammalian cells), after which the recombinant protein can bepurified and used to generate a monoclonal or polyclonal antibodypreparation that specifically bind the ovarian cancer marker polypeptideused to generate the antibody according to the invention.

One of skill in the art will realize that the generation of two or moredifferent sets of monoclonal or polyclonal antibodies maximizes thelikelihood of obtaining an antibody with the specificity and affinityrequired for its intended use (e.g., ELISA, immunohistochemistry, invivo imaging, immunotoxin therapy). The antibodies are tested for theirdesired activity by known methods, in accordance with the purpose forwhich the antibodies are to be used (e.g., ELISA, immunohistochemistry,immunotherapy, etc.; for further guidance on the generation and testingof antibodies, see, e.g., Greenfield, 2014 (Greenfield, 2014)). Forexample, the antibodies may be tested in ELISA assays or, Western blots,immunohistochemical staining of formalin-fixed cancers or frozen tissuesections. After their initial in vitro characterization, antibodiesintended for therapeutic or in vivo diagnostic use are tested accordingto known clinical testing methods.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a substantially homogeneous population of antibodies,i.e.; the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. The monoclonal antibodies herein specifically include“chimeric” antibodies in which a portion of the heavy and/or light chainis identical with or homologous to corresponding sequences in antibodiesderived from a particular species or belonging to a particular antibodyclass or subclass, while the remainder of the chain(s) is identical withor homologous to corresponding sequences in antibodies derived fromanother species or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired antagonistic activity (U.S. Pat. No. 4,816,567, which is herebyincorporated in its entirety).

Monoclonal antibodies of the invention may be prepared using hybridomamethods. In a hybridoma method, a mouse or other appropriate host animalis typically immunized with an immunizing agent to elicit lymphocytesthat produce or are capable of producing antibodies that willspecifically bind to the immunizing agent. Alternatively, thelymphocytes may be immunized in vitro.

The monoclonal antibodies may also be made by recombinant DNA methods,such as those described in U.S. Pat. No. 4,816,567. DNA encoding themonoclonal antibodies of the invention can be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies).

In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly Fabfragments, can be accomplished using routine techniques known in theart. For instance, digestion can be performed using papain. Examples ofpapain digestion are described in WO 94/29348 and U.S. Pat. No.4,342,566. Papain digestion of antibodies typically produces twoidentical antigen binding fragments, called Fab fragments, each with asingle antigen binding site, and a residual Fc fragment. Pepsintreatment yields a F(ab′)2 fragment and a pFc′ fragment.

The antibody fragments, whether attached to other sequences or not, canalso include insertions, deletions, substitutions, or other selectedmodifications of particular regions or specific amino acids residues,provided the activity of the fragment is not significantly altered orimpaired compared to the non-modified antibody or antibody fragment.These modifications can provide for some additional property, such as toremove/add amino acids capable of disulfide bonding, to increase itsbio-longevity, to alter its secretory characteristics, etc. In any case,the antibody fragment must possess a bioactive property, such as bindingactivity, regulation of binding at the binding domain, etc. Functionalor active regions of the antibody may be identified by mutagenesis of aspecific region of the protein, followed by expression and testing ofthe expressed polypeptide. Such methods are readily apparent to askilled practitioner in the art and can include site-specificmutagenesis of the nucleic acid encoding the antibody fragment.

The antibodies of the invention may further comprise humanizedantibodies or human antibodies. Humanized forms of non-human (e.g.,murine) antibodies are chimeric immunoglobulins, immunoglobulin chainsor fragments thereof (such as Fv, Fab, Fab′ or other antigen-bindingsubsequences of antibodies) which contain minimal sequence derived fromnon-human immunoglobulin. Humanized antibodies include humanimmunoglobulins (recipient antibody) in which residues from acomplementary determining region (CDR) of the recipient are replaced byresidues from a CDR of a non-human species (donor antibody) such asmouse, rat or rabbit having the desired specificity, affinity andcapacity. In some instances, Fv framework (FR) residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin.

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed by substituting rodent CDRs or CDR sequencesfor the corresponding sequences of a human antibody. Accordingly, such“humanized” antibodies are chimeric antibodies (U.S. Pat. No.4,816,567), wherein substantially less than an intact human variabledomain has been substituted by the corresponding sequence from anon-human species. In practice, humanized antibodies are typically humanantibodies in which some CDR residues and possibly some FR residues aresubstituted by residues from analogous sites in rodent antibodies.

Transgenic animals (e.g., mice) that are capable, upon immunization, ofproducing a full repertoire of human antibodies in the absence ofendogenous immunoglobulin production can be employed. For example, ithas been described that the homozygous deletion of the antibody heavychain joining region gene in chimeric and germ-line mutant mice resultsin complete inhibition of endogenous antibody production. Transfer ofthe human germ-line immunoglobulin gene array in such germ-line mutantmice will result in the production of human antibodies upon antigenchallenge. Human antibodies can also be produced in phage displaylibraries.

Antibodies of the invention are preferably administered to a subject ina pharmaceutically acceptable carrier. Typically, an appropriate amountof a pharmaceutically-acceptable salt is used in the formulation torender the formulation isotonic. Examples of thepharmaceutically-acceptable carrier include saline, Ringer's solutionand dextrose solution. The pH of the solution is preferably from about 5to about 8, and more preferably from about 7 to about 7.5. Furthercarriers include sustained release preparations such as semipermeablematrices of solid hydrophobic polymers containing the antibody, whichmatrices are in the form of shaped articles, e.g., films, liposomes ormicroparticles. It will be apparent to those persons skilled in the artthat certain carriers may be more preferable depending upon, forinstance, the route of administration and concentration of antibodybeing administered.

The antibodies can be administered to the subject, patient, or cell byinjection (e.g., intravenous, intraperitoneal, subcutaneous,intramuscular), or by other methods such as infusion that ensure itsdelivery to the bloodstream in an effective form. The antibodies mayalso be administered by intratumoral or peritumoral routes, to exertlocal as well as systemic therapeutic effects. Local or intravenousinjection is preferred.

Effective dosages and schedules for administering the antibodies may bedetermined empirically, and making such determinations is within theskill in the art. Those skilled in the art will understand that thedosage of antibodies that must be administered will vary depending on,for example, the subject that will receive the antibody, the route ofadministration, the particular type of antibody used and other drugsbeing administered. A typical daily dosage of the antibody used alonemight range from about 1 (μg/kg to up to 100 mg/kg of body weight ormore per day, depending on the factors mentioned above. Followingadministration of an antibody, preferably for treating ovarian cancer,the efficacy of the therapeutic antibody can be assessed in various wayswell known to the skilled practitioner. For instance, the size, number,and/or distribution of cancer in a subject receiving treatment may bemonitored using standard tumor imaging techniques. Atherapeutically-administered antibody that arrests tumor growth, resultsin tumor shrinkage, and/or prevents the development of new tumors,compared to the disease course that would occur in the absence ofantibody administration, is an efficacious antibody for treatment ofcancer.

It is a further aspect of the invention to provide a method forproducing a soluble T-cell receptor (sTCR) recognizing a specificpeptide-MHC complex. Such soluble T-cell receptors can be generated fromspecific T-cell clones, and their affinity can be increased bymutagenesis targeting the complementarity-determining regions. For thepurpose of T-cell receptor selection, phage display can be used (US2010/0113300, (Liddy et al., 2012)). For the purpose of stabilization ofT-cell receptors during phage display and in case of practical use asdrug, alpha and beta chain can be linked e.g. by non-native disulfidebonds, other covalent bonds (single-chain T-cell receptor), or bydimerization domains (Boulter et al., 2003; Card et al., 2004; Willcoxet al., 1999). The T-cell receptor can be linked to toxins, drugs,cytokines (see, for example, US 2013/0115191), domains recruitingeffector cells such as an anti-CD3 domain, etc., in order to executeparticular functions on target cells. Moreover, it could be expressed inT cells used for adoptive transfer. Further information can be found inWO 2004/033685A1 and WO 2004/074322A1. A combination of sTCRs isdescribed in WO 2012/056407A1. Further methods for the production aredisclosed in WO 2013/057586A1.

In addition, the peptides and/or the TCRs or antibodies or other bindingmolecules of the present invention can be used to verify a pathologist'sdiagnosis of a cancer based on a biopsied sample.

The antibodies or TCRs may also be used for in vivo diagnostic assays.Generally, the antibody is labeled with a radionucleotide (such as¹¹¹In, ⁹⁹Tc, ¹⁴C, ¹³¹I, ³H, ³²P or ³⁵S) so that the tumor can belocalized using immunoscintiography. In one embodiment, antibodies orfragments thereof bind to the extracellular domains of two or moretargets of a protein selected from the group consisting of theabove-mentioned proteins, and the affinity value (Kd) is less than 1×10μM.

Antibodies for diagnostic use may be labeled with probes suitable fordetection by various imaging methods. Methods for detection of probesinclude, but are not limited to, fluorescence, light, confocal andelectron microscopy; magnetic resonance imaging and spectroscopy;fluoroscopy, computed tomography and positron emission tomography.

Suitable probes include, but are not limited to, fluorescein, rhodamine,eosin and other fluorophores, radioisotopes, gold, gadolinium and otherlanthanides, paramagnetic iron, fluorine-18 and other positron-emittingradionuclides. Additionally, probes may be bi- or multi-functional andbe detectable by more than one of the methods listed. These antibodiesmay be directly or indirectly labeled with said probes. Attachment ofprobes to the antibodies includes covalent attachment of the probe,incorporation of the probe into the antibody, and the covalentattachment of a chelating compound for binding of probe, amongst otherswell recognized in the art. For immunohistochemistry, the disease tissuesample may be fresh or frozen or may be embedded in paraffin and fixedwith a preservative such as formalin. The fixed or embedded sectioncontains the sample are contacted with a labeled primary antibody andsecondary antibody, wherein the antibody is used to detect theexpression of the proteins in situ.

Another aspect of the present invention includes an in vitro method forproducing activated T cells, the method comprising contacting in vitro Tcells with antigen loaded human MHC molecules expressed on the surfaceof a suitable antigen-presenting cell for a period of time sufficient toactivate the T cell in an antigen specific manner, wherein the antigenis a peptide according to the invention. Preferably a sufficient amountof the antigen is used with an antigen-presenting cell.

Preferably the mammalian cell lacks or has a reduced level or functionof the TAP peptide transporter. Suitable cells that lack the TAP peptidetransporter include T2, RMA-S and Drosophila cells. TAP is thetransporter associated with antigen processing.

The human peptide loading deficient cell line T2 is available from theAmerican Type Culture Collection, 12301 Parklawn Drive, Rockville, Md.20852, USA under Catalogue No CRL 1992; the Drosophila cell lineSchneider line 2 is available from the ATCC under Catalogue No CRL19863; the mouse RMA-S cell line is described in Ljunggren et al.(Ljunggren and Karre, 1985).

Preferably, before transfection the host cell expresses substantially noMHC class I molecules. It is also preferred that the stimulator cellexpresses a molecule important for providing a co-stimulatory signal forT-cells such as any of B7.1, B7.2, ICAM-1 and LFA 3. The nucleic acidsequences of numerous MHC class I molecules and of the co-stimulatormolecules are publicly available from the GenBank and EMBL databases.

In case of a MHC class I epitope being used as an antigen, the T cellsare CD8-positive T cells.

If an antigen-presenting cell is transfected to express such an epitope,preferably the cell comprises an expression vector capable of expressinga peptide containing SEQ ID NO: 1 to SEQ ID NO: 640, or a variant aminoacid sequence thereof.

A number of other methods may be used for generating T cells in vitro.For example, autologous tumor-infiltrating lymphocytes can be used inthe generation of CTL. Plebanski et al. (Plebanski et al., 1995) madeuse of autologous peripheral blood lymphocytes (PLBs) in the preparationof T cells. Furthermore, the production of autologous T cells by pulsingdendritic cells with peptide or polypeptide, or via infection withrecombinant virus is possible. Also, B cells can be used in theproduction of autologous T cells. In addition, macrophages pulsed withpeptide or polypeptide, or infected with recombinant virus, may be usedin the preparation of autologous T cells. S.

Walter et al. (Walter et al., 2003) describe the in vitro priming of Tcells by using artificial antigen presenting cells (aAPCs), which isalso a suitable way for generating T cells against the peptide ofchoice. In the present invention, aAPCs were generated by the couplingof preformed MHC:peptide complexes to the surface of polystyreneparticles (microbeads) by biotin:streptavidin biochemistry. This systempermits the exact control of the MHC density on aAPCs, which allows toselectively elicit high- or low-avidity antigen-specific T cellresponses with high efficiency from blood samples. Apart fromMHC:peptide complexes, aAPCs should carry other proteins withco-stimulatory activity like anti-CD28 antibodies coupled to theirsurface. Furthermore, such aAPC-based systems often require the additionof appropriate soluble factors, e. g. cytokines, like interleukin-12.

Allogeneic cells may also be used in the preparation of T cells and amethod is described in detail in WO 97/26328, incorporated herein byreference. For example, in addition to Drosophila cells and T2 cells,other cells may be used to present antigens such as CHO cells,baculovirus-infected insect cells, bacteria, yeast, vaccinia-infectedtarget cells. In addition, plant viruses may be used (see, for example,Porta et al. (Porta et al., 1994) which describes the development ofcowpea mosaic virus as a high-yielding system for the presentation offoreign peptides.

The activated T cells that are directed against the peptides of theinvention are useful in therapy. Thus, a further aspect of the inventionprovides activated T cells obtainable by the foregoing methods of theinvention.

Activated T cells, which are produced by the above method, willselectively recognize a cell that aberrantly expresses a polypeptidethat comprises an amino acid sequence of SEQ ID NO: 1 to SEQ ID NO 640.

Preferably, the T cell recognizes the cell by interacting through itsTCR with the HLA/peptide-complex (for example, binding). The T cells areuseful in a method of killing target cells in a patient whose targetcells aberrantly express a polypeptide comprising an amino acid sequenceof the invention wherein the patient is administered an effective numberof the activated T cells. The T cells that are administered to thepatient may be derived from the patient and activated as described above(i.e. they are autologous T cells). Alternatively, the T cells are notfrom the patient but are from another individual. Of course, it ispreferred if the individual is a healthy individual. By “healthyindividual” the inventors mean that the individual is generally in goodhealth, preferably has a competent immune system and, more preferably,is not suffering from any disease that can be readily tested for, anddetected.

In vivo, the target cells for the CD8-positive T cells according to thepresent invention can be cells of the tumor (which sometimes express MHCclass II) and/or stromal cells surrounding the tumor (tumor cells)(which sometimes also express MHC class II; (Dengjel et al., 2006)).

The T cells of the present invention may be used as active ingredientsof a therapeutic composition. Thus, the invention also provides a methodof killing target cells in a patient whose target cells aberrantlyexpress a polypeptide comprising an amino acid sequence of theinvention, the method comprising administering to the patient aneffective number of T cells as defined above.

By “aberrantly expressed” the inventors also mean that the polypeptideis over-expressed compared to normal levels of expression or that thegene is silent in normal (healthy) tissues. By “over-expressed” theinventors mean that the polypeptide is present at a level at least1.2-fold of that present in normal tissue; preferably at least 2-fold,and more preferably at least 5-fold or 10-fold the level present innormal tissue.

T cells may be obtained by methods known in the art, e.g. thosedescribed above.

Protocols for this so-called adoptive transfer of T cells are well knownin the art. Reviews can be found in: Gattioni et al. and Morgan et al.(Gattinoni et al., 2006; Morgan et al., 2006).

Another aspect of the present invention includes the use of the peptidescomplexed with MHC to generate a T-cell receptor whose nucleic acid iscloned and is introduced into a host cell, preferably a T cell. Thisengineered T cell can then be transferred to a patient for therapy ofcancer.

Any molecule of the invention, i.e. the peptide, nucleic acid, antibody,expression vector, cell, activated T cell, T-cell receptor or thenucleic acid encoding it, is useful for the treatment of disorders,characterized by cells escaping an immune response. Therefore, anymolecule of the present invention may be used as medicament or in themanufacture of a medicament. The molecule may be used by itself orcombined with other molecule(s) of the invention or (a) knownmolecule(s).

The present invention further provides a medicament that is useful intreating cancer, in particular ovarian cancer and other malignancies.

The present invention is further directed at a kit comprising:

(a) a container containing a pharmaceutical composition as describedabove, in solution or in lyophilized form;

(b) optionally a second container containing a diluent or reconstitutingsolution for the lyophilized formulation; and

(c) optionally, instructions for (i) use of the solution or (ii)reconstitution and/or use of the lyophilized formulation.

The kit may further comprise one or more of (iii) a buffer, (iv) adiluent, (v) a filter, (vi) a needle, or (v) a syringe. The container ispreferably a bottle, a vial, a syringe or test tube; and it may be amulti-use container. The pharmaceutical composition is preferablylyophilized.

Kits of the present invention preferably comprise a lyophilizedformulation of the present invention in a suitable container andinstructions for its reconstitution and/or use. Suitable containersinclude, for example, bottles, vials (e.g. dual chamber vials), syringes(such as dual chamber syringes) and test tubes. The container may beformed from a variety of materials such as glass or plastic. Preferablythe kit and/or container contain/s instructions on or associated withthe container that indicates directions for reconstitution and/or use.For example, the label may indicate that the lyophilized formulation isto be reconstituted to peptide concentrations as described above. Thelabel may further indicate that the formulation is useful or intendedfor subcutaneous administration.

The container holding the formulation may be a multi-use vial, whichallows for repeat administrations (e.g., from 2-6 administrations) ofthe reconstituted formulation. The kit may further comprise a secondcontainer comprising a suitable diluent (e.g., sodium bicarbonatesolution).

Upon mixing of the diluent and the lyophilized formulation, the finalpeptide concentration in the reconstituted formulation is preferably atleast 0.15 mg/mL/peptide (=75 μg) and preferably not more than 3mg/mL/peptide (=1500 μg). The kit may further include other materialsdesirable from a commercial and user standpoint, including otherbuffers, diluents, filters, needles, syringes, and package inserts withinstructions for use.

Kits of the present invention may have a single container that containsthe formulation of the pharmaceutical compositions according to thepresent invention with or without other components (e.g., othercompounds or pharmaceutical compositions of these other compounds) ormay have distinct container for each component.

Preferably, kits of the invention include a formulation of the inventionpackaged for use in combination with the co-administration of a secondcompound (such as adjuvants (e.g. GM-CSF), a chemotherapeutic agent, anatural product, a hormone or antagonist, an anti-angiogenesis agent orinhibitor, an apoptosis-inducing agent or a chelator) or apharmaceutical composition thereof. The components of the kit may bepre-complexed or each component may be in a separate distinct containerprior to administration to a patient. The components of the kit may beprovided in one or more liquid solutions, preferably, an aqueoussolution, more preferably, a sterile aqueous solution. The components ofthe kit may also be provided as solids, which may be converted intoliquids by addition of suitable solvents, which are preferably providedin another distinct container.

The container of a therapeutic kit may be a vial, test tube, flask,bottle, syringe, or any other means of enclosing a solid or liquid.Usually, when there is more than one component, the kit will contain asecond vial or other container, which allows for separate dosing. Thekit may also contain another container for a pharmaceutically acceptableliquid. Preferably, a therapeutic kit will contain an apparatus (e.g.,one or more needles, syringes, eye droppers, pipette, etc.), whichenables administration of the agents of the invention that arecomponents of the present kit.

The present formulation is one that is suitable for administration ofthe peptides by any acceptable route such as oral (enteral), nasal,ophthal, subcutaneous, intradermal, intramuscular, intravenous ortransdermal. Preferably, the administration is s.c., and most preferablyi.d. administration may be by infusion pump.

Since the peptides of the invention were isolated from ovarian cancer,the medicament of the invention is preferably used to treat ovariancancer.

The present invention further relates to a method for producing apersonalized pharmaceutical for an individual patient comprisingmanufacturing a pharmaceutical composition comprising at least onepeptide selected from a warehouse of pre-screened TUMAPs, wherein the atleast one peptide used in the pharmaceutical composition is selected forsuitability in the individual patient. In one embodiment, thepharmaceutical composition is a vaccine. The method could also beadapted to produce T cell clones for down-stream applications, such asTCR isolations, or soluble antibodies, and other treatment options.

A “personalized pharmaceutical” shall mean specifically tailoredtherapies for one individual patient that will only be used for therapyin such individual patient, including actively personalized cancervaccines and adoptive cellular therapies using autologous patienttissue.

As used herein, the term “warehouse” shall refer to a group or set ofpeptides that have been pre-screened for immunogenicity and/orover-presentation in a particular tumor type. The term “warehouse” isnot intended to imply that the particular peptides included in thevaccine have been pre-manufactured and stored in a physical facility,although that possibility is contemplated. It is expressly contemplatedthat the peptides may be manufactured de novo for each individualizedvaccine produced, or may be pre-manufactured and stored. The warehouse(e.g. in the form of a database) is composed of tumor-associatedpeptides which were highly overexpressed in the tumor tissue of ovariancancer patients with various HLA-A HLA-B and HLA-C alleles. It maycontain MHC class I and MHC class II peptides or elongated MHC class Ipeptides. In addition to the tumor associated peptides collected fromseveral ovarian cancer tissues, the warehouse may contain HLA-A*02 andHLA-A*24 marker peptides. These peptides allow comparison of themagnitude of T-cell immunity induced by TUMAPS in a quantitative mannerand hence allow important conclusion to be drawn on the capacity of thevaccine to elicit anti-tumor responses. Secondly, they function asimportant positive control peptides derived from a “non-self” antigen inthe case that any vaccine-induced T-cell responses to TUMAPs derivedfrom “self” antigens in a patient are not observed. And thirdly, it mayallow conclusions to be drawn, regarding the status of immunocompetenceof the patient.

TUMAPs for the warehouse are identified by using an integratedfunctional genomics approach combining gene expression analysis, massspectrometry, and T-cell immunology (XPresident®). The approach assuresthat only TUMAPs truly present on a high percentage of tumors but not oronly minimally expressed on normal tissue, are chosen for furtheranalysis. For initial peptide selection, ovarian cancer samples frompatients and blood from healthy donors were analyzed in a stepwiseapproach:

1. HLA ligands from the malignant material were identified by massspectrometry

2. Genome-wide messenger ribonucleic acid (mRNA) expression analysis wasused to identify genes over-expressed in the malignant tissue (ovariancancer) compared with a range of normal organs and tissues

3. Identified HLA ligands were compared to gene expression data.Peptides over-presented or selectively presented on tumor tissue,preferably encoded by selectively expressed or over-expressed genes asdetected in step 2 were considered suitable TUMAP candidates for amulti-peptide vaccine.

4. Literature research was performed in order to identify additionalevidence supporting the relevance of the identified peptides as TUMAPs

5. The relevance of over-expression at the mRNA level was confirmed byredetection of selected TUMAPs from step 3 on tumor tissue and lack of(or infrequent) detection on healthy tissues.

6. In order to assess, whether an induction of in vivo T-cell responsesby the selected peptides may be feasible, in vitro immunogenicity assayswere performed using human T cells from healthy donors as well as fromovarian cancer patients.

In an aspect, the peptides are pre-screened for immunogenicity beforebeing included in the warehouse. By way of example, and not limitation,the immunogenicity of the peptides included in the warehouse isdetermined by a method comprising in vitro T-cell priming throughrepeated stimulations of CD8+ T cells from healthy donors withartificial antigen presenting cells loaded with peptide/MHC complexesand anti-CD28 antibody.

This method is preferred for rare cancers and patients with a rareexpression profile. In contrast to multi-peptide cocktails with a fixedcomposition as currently developed, the warehouse allows a significantlyhigher matching of the actual expression of antigens in the tumor withthe vaccine. Selected single or combinations of several “off-the-shelf”peptides will be used for each patient in a multitarget approach. Intheory an approach based on selection of e.g. 5 different antigenicpeptides from a library of 50 would already lead to approximately 17million possible drug product (DP) compositions.

In an aspect, the peptides are selected for inclusion in the vaccinebased on their suitability for the individual patient based on themethod according to the present invention as described herein, or asbelow.

The HLA phenotype, transcriptomic and peptidomic data is gathered fromthe patient's tumor material, and blood samples to identify the mostsuitable peptides for each patient containing “warehouse” andpatient-unique (i.e. mutated) TUMAPs. Those peptides will be chosen,which are selectively or over-expressed in the patients' tumor and,where possible, show strong in vitro immunogenicity if tested with thepatients' individual PBMCs.

Preferably, the peptides included in the vaccine are identified by amethod comprising: (a) identifying tumor-associated peptides (TUMAPs)presented by a tumor sample from the individual patient; (b) comparingthe peptides identified in (a) with a warehouse (database) of peptidesas described above; and (c) selecting at least one peptide from thewarehouse (database) that correlates with a tumor-associated peptideidentified in the patient. For example, the TUMAPs presented by thetumor sample are identified by: (a1) comparing expression data from thetumor sample to expression data from a sample of normal tissuecorresponding to the tissue type of the tumor sample to identifyproteins that are over-expressed or aberrantly expressed in the tumorsample; and (a2) correlating the expression data with sequences of MHCligands bound to MHC class I and/or class II molecules in the tumorsample to identify MHC ligands derived from proteins over-expressed oraberrantly expressed by the tumor. Preferably, the sequences of MHCligands are identified by eluting bound peptides from MHC moleculesisolated from the tumor sample, and sequencing the eluted ligands.Preferably, the tumor sample and the normal tissue are obtained from thesame patient.

In addition to, or as an alternative to, selecting peptides using awarehousing (database) model, TUMAPs may be identified in the patient denovo, and then included in the vaccine. As one example, candidate TUMAPsmay be identified in the patient by (a1) comparing expression data fromthe tumor sample to expression data from a sample of normal tissuecorresponding to the tissue type of the tumor sample to identifyproteins that are over-expressed or aberrantly expressed in the tumorsample; and (a2) correlating the expression data with sequences of MHCligands bound to MHC class I and/or class II molecules in the tumorsample to identify MHC ligands derived from proteins over-expressed oraberrantly expressed by the tumor. As another example, proteins may beidentified containing mutations that are unique to the tumor samplerelative to normal corresponding tissue from the individual patient, andTUMAPs can be identified that specifically target the mutation. Forexample, the genome of the tumor and of corresponding normal tissue canbe sequenced by whole genome sequencing: For discovery of non-synonymousmutations in the protein-coding regions of genes, genomic DNA and RNAare extracted from tumor tissues and normal non-mutated genomic germlineDNA is extracted from peripheral blood mononuclear cells (PBMCs). Theapplied NGS approach is confined to the re-sequencing of protein codingregions (exome re-sequencing). For this purpose, exonic DNA from humansamples is captured using vendor-supplied target enrichment kits,followed by sequencing with e.g. a HiSeq2000 (Illumina). Additionally,tumor mRNA is sequenced for direct quantification of gene expression andvalidation that mutated genes are expressed in the patients' tumors. Theresultant millions of sequence reads are processed through softwarealgorithms. The output list contains mutations and gene expression.Tumor-specific somatic mutations are determined by comparison with thePBMC-derived germline variations and prioritized. The de novo identifiedpeptides can then be tested for immunogenicity as described above forthe warehouse, and candidate TUMAPs possessing suitable immunogenicityare selected for inclusion in the vaccine.

In one exemplary embodiment, the peptides included in the vaccine areidentified by: (a) identifying tumor-associated peptides (TUMAPs)presented by a tumor sample from the individual patient by the method asdescribed above; (b) comparing the peptides identified in a) with awarehouse of peptides that have been prescreened for immunogenicity andoverpresentation in tumors as compared to corresponding normal tissue;(c) selecting at least one peptide from the warehouse that correlateswith a tumor-associated peptide identified in the patient; and (d)optionally, selecting at least one peptide identified de novo in (a)confirming its immunogenicity.

In one exemplary embodiment, the peptides included in the vaccine areidentified by: (a) identifying tumor-associated peptides (TUMAPs)presented by a tumor sample from the individual patient; and (b)selecting at least one peptide identified de novo in (a) and confirmingits immunogenicity.

Once the peptides for a personalized peptide based vaccine are selected,the vaccine is produced. The vaccine preferably is a liquid formulationconsisting of the individual peptides dissolved in between 20-40% DMSO,preferably about 30-35% DMSO, such as about 33% DMSO.

Each peptide to be included into a product is dissolved in DMSO. Theconcentration of the single peptide solutions has to be chosen dependingon the number of peptides to be included into the product. The singlepeptide-DMSO solutions are mixed in equal parts to achieve a solutioncontaining all peptides to be included in the product with aconcentration of ˜2.5 mg/ml per peptide. The mixed solution is thendiluted 1:3 with water for injection to achieve a concentration of 0.826mg/ml per peptide in 33% DMSO. The diluted solution is filtered througha 0.22 μm sterile filter. The final bulk solution is obtained.

Final bulk solution is filled into vials and stored at −20° C. untiluse. One vial contains 700 μL solution, containing 0.578 mg of eachpeptide. Of this, 500 μL (approx. 400 μg per peptide) will be appliedfor intradermal injection.

In addition to being useful for treating cancer, the peptides of thepresent invention are also useful as diagnostics. Since the peptideswere generated from ovarian cancer samples and since it was determinedthat these peptides are not or at lower levels present in normaltissues, these peptides can be used to diagnose the presence of acancer.

The presence of claimed peptides on tissue biopsies in blood samples canassist a pathologist in diagnosis of cancer. Detection of certainpeptides by means of antibodies, mass spectrometry or other methodsknown in the art can tell the pathologist that the tissue sample ismalignant or inflamed or generally diseased, or can be used as abiomarker for ovarian cancer. Presence of groups of peptides can enableclassification or sub-classification of diseased tissues.

The detection of peptides on diseased tissue specimen can enable thedecision about the benefit of therapies involving the immune system,especially if T-lymphocytes are known or expected to be involved in themechanism of action. Loss of MHC expression is a well describedmechanism by which infected of malignant cells escapeimmuno-surveillance. Thus, presence of peptides shows that thismechanism is not exploited by the analyzed cells.

The peptides of the present invention might be used to analyzelymphocyte responses against those peptides such as T cell responses orantibody responses against the peptide or the peptide complexed to MHCmolecules. These lymphocyte responses can be used as prognostic markersfor decision on further therapy steps. These responses can also be usedas surrogate response markers in immunotherapy approaches aiming toinduce lymphocyte responses by different means, e.g. vaccination ofprotein, nucleic acids, autologous materials, adoptive transfer oflymphocytes. In gene therapy settings, lymphocyte responses againstpeptides can be considered in the assessment of side effects. Monitoringof lymphocyte responses might also be a valuable tool for follow-upexaminations of transplantation therapies, e.g. for the detection ofgraft versus host and host versus graft diseases.

The present invention will now be described in the following exampleswhich describe preferred embodiments thereof, and with reference to theaccompanying figures, nevertheless, without being limited thereto. Forthe purposes of the present invention, all references as cited hereinare incorporated by reference in their entireties.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1AE show the over-presentation of various peptides in normaltissues (white bars) and ovarian cancer (black bars). FIG. 1A) Genesymbol: CLSR2, Peptide: VLVSDGVHSV (SEQ ID NO.: 6); Tissues from left toright: 1 adipose tissues, 3 adrenal glands, 6 arteries, 5 bone marrows,7 brains, 3 breasts, 1 central nerve, 13 colons, 1 duodenum, 8 esophagi,2 gallbladders, 5 hearts, 16 kidneys, 2 lymph nodes, 21 livers, 46lungs, 1 lymph node metastasis, 4 leukocyte samples, 7 pancreas, 4peripheral nerves, 1 peritoneum, 3 pituitary glands, 2 placentas, 3pleuras, 3 prostates, 6 recti, 7 salivary glands, 3 skeletal muscles, 5skins, 2 small intestines, 4 spleens, 7 stomachs, 4 testis, 3 thymi, 4thyroid glands, 7 tracheas, 3 ureters, 6 urinary bladders, 2 uteri, 2veins, 3 ovaries, 20° C. The peptide has additionally been detected on1/6 breast cancers, 1/2 Merkel cell carcinomas, 3/17 esophageal cancers,3/91 lung cancers, 10/29 brain cancers, 1/22 renal cancers and 1/15small cell lung cancers (not shown). FIG. 1B) Gene symbol: CCNA1,Peptide: SLMEPPAVLLL (SEQ ID NO.: 1); Tissues from left to right: 1adipose tissues, 3 adrenal glands, 6 arteries, 5 bone marrows, 7 brains,3 breasts, 1 central nerve, 13 colons, 1 duodenum, 8 esophagi, 2gallbladders, 5 hearts, 16 kidneys, 2 lymph nodes, 21 livers, 46 lungs,1 lymph node metastasis, 4 leukocyte samples, 7 pancreas, 4 peripheralnerves, 1 peritoneum, 3 pituitary glands, 2 placentas, 3 pleuras, 3prostates, 6 recti, 7 salivary glands, 3 skeletal muscles, 5 skins, 2small intestines, 4 spleens, 7 stomachs, 4 testis, 3 thymi, 4 thyroidglands, 7 tracheas, 3 ureters, 6 urinary bladders, 2 uteri, 2 veins, 3ovaries, 20° C. The peptide has additionally been detected on 1/2 AMLs,1/28 colorectal cancers, 2/17 esophageal cancers, 7/91 lung cancers,1/29 brain cancers, 1/22 renal cancers and 2/15 small cell lung cancers(not shown). FIG. 1C) Gene symbol: VTCN1, Peptide: ALLPLSPYL (SEQ IDNO.: 427); Tissues from left to right: 1 adipose tissues, 3 adrenalglands, 6 arteries, 5 bone marrows, 7 brains, 3 breasts, 1 centralnerve, 13 colons, 1 duodenum, 8 esophagi, 2 gallbladders, 5 hearts, 16kidneys, 2 lymph nodes, 21 livers, 46 lungs, 1 lymph node metastasis, 4leukocyte samples, 7 pancreas, 4 peripheral nerves, 1 peritoneum, 3pituitary glands, 2 placentas, 3 pleuras, 3 prostates, 6 recti, 7salivary glands, 3 skeletal muscles, 5 skins, 2 small intestines, 4spleens, 7 stomachs, 4 testis, 3 thymi, 4 thyroid glands, 7 tracheas, 3ureters, 6 urinary bladders, 2 uteri, 2 veins, 3 ovaries, 20° C. Thepeptide has additionally been detected on 4/43 prostate cancers, 3/6breast cancers, 4/16 liver cancers, 1/17 esophageal cancers, 4/19pancreatic cancers, 19/91 lung cancers, 1/15 small cell lung cancers,1/4 urinary bladder cancers and 3/4 uterine cancers (not shown). FIG.1D) Gene symbol: AP1B1, Peptide: FLDTLKDLI SEQ ID NO.: 514); Tissuesfrom left to right: 6 cell lines (1 lymphocytic, 1 kidney, 1 pancreatic,2 PBMCs, K562-A2), 4 normal tissues (2 bone marrows, 2 spleens), 49cancer tissues (1 breast cancer, 3 colon cancers, 2 esophageal cancers,1 gallbladder cancer, 2 leukemias, 3 liver cancers, 21 lung cancers, 7ovarian cancers, 23 rectum cancers, 1 skin cancer, 4 stomach cancers, 1testis cancer, 1 urinary bladder cancer). The normal tissue panel andthe cancer cell lines and xenografts tested were the same as in FIG.1A-1C, consisting of 1 adipose tissue, 3 adrenal glands, 6 arteries, 5bone marrows, 7 brains, 3 breasts, 1 central nerve, 13 colons, 1duodenum, 8 esophagi, 2 gallbladders, 5 hearts, 16 kidneys, 2 lymphnodes, 21 livers, 46 lungs, 1 lymph node metastasis, 4 leukocytesamples, 7 pancreas, 4 peripheral nerves, 1 peritoneum, 3 pituitaryglands, 2 placentas, 3 pleuras, 3 prostates, 6 recti, 7 salivary glands,3 skeletal muscles, 5 skins, 2 small intestines, 4 spleens, 7 stomachs,4 testes, 3 thymi, 4 thyroid glands, 7 tracheas, 3 ureters, 6 urinarybladders, 2 uteri, 2 veins, 3 ovaries, 20° C. The peptide hasadditionally been detected on 2/12 chronic lymphocytic leukemias, 5/28colorectal cancers, 2/16 liver cancers, 1/2 melanomas, 2/17 esophagealcancers, 17/91 lung cancers, 4/46 stomach cancers, 4/15 small cell lungcancers and 1/4 urinary bladder cancers. Discrepancies regarding thelist of tumor types between FIG. 1D and table 4 might be due to the morestringent selection criteria applied in table 4 (for details pleaserefer to table 4). FIG. 1D shows all samples with detectablepresentation of the peptide Y, regardless of over-presentationparameters and technical sample quality check. FIG. 1E) Gene symbol(s):CELSR2, Peptide: VLVSDGVHSV (SEQ ID NO.: 6). Tissues from left to right:6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels,10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroidglands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 smallintestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands,16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancersamples. The peptide has additionally been found on 15/34 brain cancers,3/18 breast cancers, 3/18 esophageal cancers, 4/12 head and neckcancers, 1/23 kidney cancers, 6/107 lung cancers, 5/18 skin cancers,5/15 urinary bladder cancers, 3/16 uterus cancers. FIG. 1F) Genesymbol(s): SUCO, Peptide: LLLDITPEI (SEQ ID NO.: 143). Tissues from leftto right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 bloodvessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroidglands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 smallintestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands,16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancersamples. The peptide has additionally been found on 2/34 brain cancers,4/18 breast cancers, 2/18 esophageal cancers, 1/12 head and neckcancers, 2/21 liver cancers, 6/107 lung cancers, 2/18 skin cancers, 1/45stomach cancers, 2/15 urinary bladder cancers. FIG. 1G) Gene symbol(s):PLAUR, Peptide: RLWEEGEELEL (SEQ ID NO.: 150). Tissues from left toright: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 bloodvessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroidglands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 smallintestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands,16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancersamples. The peptide has additionally been found on 4/17 gallbladder andbile duct cancers, 1/18 breast cancers, 1/29 colon cancers, 2/18esophageal cancers, 1/12 head and neck cancers, 10/107 lung cancers,2/18 skin cancers, 1/16 uterus cancers. FIG. 1H) Gene symbol(s): HEATR2,Peptide: SLNDEVPEV (SEQ ID NO.: 157). Tissues from left to right: 6adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders,16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymphnodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. Thepeptide has additionally been found on 1/17 bile duct cancers, 5/34brain cancers, 1/18 breast cancers, 1/29 colon cancers, 2/18 esophagealcancers, 1/12 head and neck cancers, 2/23 kidney cancers, 1/21 livercancers, 4/107 lung cancers, 2/20 lymph node cancers, 1/18 skin cancers,1/15 urinary bladder cancers, 1/16 uterus cancers. FIG. 1I) Genesymbol(s): VTCN1, Peptide: ALLPLSPYL (SEQ ID NO.: 427). Tissues fromleft to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroidglands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovariancancer samples. The peptide has additionally been found on 7/17gallbladder and bile duct cancers, 9/18 breast cancers, 2/18 esophagealcancers, 1/12 head and neck cancers, 7/21 liver cancers, 22/107 lungcancers, 4/19 pancreas cancers, 4/87 prostate cancers, 2/15 urinarybladder cancers, 11/16 uterus cancers. FIG. 1J) Gene symbol(s): DDX11,DDX12P, LOC642846, Peptide: GLLRDEALAEV (SEQ ID NO.: 444). Tissues fromleft to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroidglands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovariancancer samples. The peptide has additionally been found on 2/18 breastcancers, 3/29 colon or rectum cancers, 1/18 esophageal cancers, 1/12head and neck cancers, 1/23 kidney cancers, 2/17 leukocytic leukemiacancers, 9/107 lung cancers, 6/20 lymph node cancers, 1/18 myeloid cellscancer, 2/18 skin cancers, 2/15 urinary bladder cancers, 1/16 uteruscancers. FIG. 1K) Gene symbol(s): KDM1B, Peptide: KLAEGLDIQL (SEQ IDNO.: 449). Tissues from left to right: 6 adipose tissues, 8 adrenalglands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitaryglands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs,5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinarybladders, 6 uteri, 20 ovarian cancer samples. The peptide hasadditionally been found on 3/29 colon or rectum cancers, 6/107 lungcancers, 1/20 lymph node cancers. FIG. 1L) Gene symbol(s): CCNA1,Peptide: SLMEPPAVLLL (SEQ ID NO.: 1). Tissues from left to right: 1cancer cell line, 1 normal tissue (1 lymph node), 45 cancer tissues (3bone marrow cancers, 1 brain cancer, 1 breast cancer, 2 esophagealcancers, 1 head and neck cancer, 1 kidney cancer, 3 leukocytic leukemiacancers, 12 lung cancers, 1 myeloid cell cancer, 11 ovarian cancers, 2urinary bladder cancers, 7 uterus cancers. The normal tissue paneltested was the same as in FIGS. 1E-1K. FIG. 1M) Gene symbol(s): CT45A5,LOC101060208, CT45A3, CT45A1, LOC101060211, CT45A6, CT45A4,LOC101060210, CT45A2, Peptide: KIFEMLEGV (SEQ ID NO.: 11). Tissues fromleft to right: 3 normal tissues (1 brain, 1 lung, 1 ureter), 21 cancertissues (1 bile duct cancer, 1 esophageal cancer, 1 liver cancer, 10lung cancers, 1 lymph node cancer, 5 ovarian cancers, 2 uterus cancers).The normal tissue panel tested was the same as in FIGS. 1E-1K. FIG. 1N)Gene symbol(s): FGFR1OP, Peptide: KLDDLTQDLTV (SEQ ID NO.: 32). Tissuesfrom left to right: 1 cell line, 1 normal tissue (1 liver), 29 cancertissues (2 bile duct cancers, 1 esophageal cancer, 2 head and neckcancers, 4 liver cancers, 4 lung cancers, 3 lymph node cancers, 8ovarian cancers, 1 prostate cancer, 1 rectum cancer, 2 urinary bladdercancers, 1 uterus cancer). The normal tissue panel tested was the sameas in FIGS. 1E-1K. FIG. 1O) Gene symbol(s): TSEN15, Peptide: FLLEDDIHVS(SEQ ID NO.: 38). Tissues from left to right: 1 primary culture, 1normal tissue (1 trachea), 28 cancer tissues (2 breast cancers, 1 headand neck cancer, 4 leukocytic leukemia cancers, 5 lung cancers, 6 lymphnode cancers, 1 myeloid cell cancer, 2 ovarian cancers, 1 rectum cancer,3 skin cancers, 2 urinary bladder cancers, 1 uterus cancer). The normaltissue panel tested was the same as in FIGS. 1E-1K. FIG. 1P) Genesymbol(s): ZNF527, ZNF829, ZNF383, ZNF850, ZNF583, Peptide: SLLEQGKEPWMV(SEQ ID NO.: 54). Tissues from left to right: 1 cell line, 18 cancertissues (2 brain cancers, 1 breast cancer, 1 gallbladder cancer, 1leukocytic leukemia cancer, 2 liver cancers, 7 lung cancers, 1 lymphnode cancer, 2 ovarian cancers, 1 urinary bladder cancer). The normaltissue panel tested was the same as in FIGS. 1E-1K. FIG. 1Q) Genesymbol(s): CAMSAP1, Peptide: TLAELQPPVQL (SEQ ID NO.: 57). Tissues fromleft to right: 4 cell lines and primary cultures, 32 cancer tissues (1bile duct cancer, 1 brain cancer, 2 esophageal cancers, 3 head and neckcancers, 2 leukocytic leukemia cancers, 1 liver cancer, 9 lung cancers,4 lymph node cancers, 5 ovarian cancers, 2 skin cancers, 1 urinarybladder cancer, 1 uterus cancer). The normal tissue panel tested was thesame as in FIGS. 1E-1K. FIG. 1R) Gene symbol(s): STK38L, Peptide:ILVEADGAWVV (SEQ ID NO.: 77). Tissues from left to right: 4 cell lines,19 cancer tissues (1 brain cancer, 2 breast cancers, 1 colon cancer, 1leukocytic leukemia cancer, 4 lung cancers, 3 lymph node cancers, 3ovarian cancers, 1 prostate cancer, 1 skin cancer, 1 urinary bladdercancer, 1 uterus cancer). The normal tissue panel tested was the same asin FIGS. 1E-1K. FIG. 1S) Gene symbol(s): PIGA, Peptide: ALNPEIVSV (SEQID NO.: 148). Tissues from left to right: 3 cell lines, 20 cancertissues (1 esophageal cancer, 2 head and neck cancers, 1 leukocyticleukemia cancer, 5 lung cancers, 3 lymph node cancers, 2 ovariancancers, 2 skin cancers, 4 urinary bladder cancers). The normal tissuepanel tested was the same as in FIGS. 1E-1K. FIG. 1T) Gene symbol(s):NPLOC4, Peptide: YLNHLEPPV (SEQ ID NO.: 166). Tissues from left toright: 2 cell lines, 20 cancer tissues (3 brain cancers, 1 breastcancer, 1 esophageal cancer, 3 leukocytic leukemia cancers, 2 livercancers, 4 lung cancers, 2 lymph node cancers, 1 myeloid cells cancer, 3ovarian cancers). The normal tissue panel tested was the same as inFIGS. 1E-1K. FIG. 1U) Gene symbol(s): RNF213, Peptide: YLMDINGKMWL (SEQID NO.: 184). Tissues from left to right: 1 cell line, 19 cancer tissues(1 breast cancer, 1 gallbladder cancer, 1 leukocytic leukemia cancer, 6lung cancers, 2 lymph node cancers, 5 ovarian cancers, 2 skin cancers, 1uterus cancer). The normal tissue panel tested was the same as in FIGS.1E-1K. FIG. 1V) Gene symbol(s): SKIL, Peptide: KTINKVPTV (SEQ ID NO.:198). Tissues from left to right: 2 cell lines and primary cultures, 1normal tissue (1 lung), 36 cancer tissues (3 brain cancers, 2 breastcancers, 2 colon cancers, 1 head and neck cancer, 1 liver cancer, 14lung cancers, 1 lymph node cancer, 8 ovarian cancers, 1 rectum cancer, 2urinary bladder cancers, 1 uterus cancer). The normal tissue paneltested was the same as in FIGS. 1E-1K. FIG. 1W) Gene symbol(s): SEC24C,Peptide: FLFPNQYVDV (SEQ ID NO.: 248). Tissues from left to right: 3cell lines and primary cultures, 1 normal tissue (1 spleen), 24 cancertissues (1 bile duct cancer, 2 breast cancers, 2 leukocytic leukemiacancers, 1 liver cancer, 9 lung cancers, 2 lymph node cancers, 3 ovariancancers, 1 prostate cancer, 2 skin cancers, 1 uterus cancer). The normaltissue panel tested was the same as in FIGS. 1E-1K. FIG. 1X) Genesymbol(s): PDIK1L, STK35, Peptide: ALLENPKMEL (SEQ ID NO.: 441). Tissuesfrom left to right: 5 cell lines and primary cultures, 1 normal tissue(1 adrenal gland), 26 cancer tissues (1 breast cancer, 1 colon cancer, 1esophageal cancer, 1 head and neck cancer, 2 liver cancers, 10 lungcancers, 5 ovarian cancers, 1 prostate cancer, 1 rectum cancer, 2urinary bladder cancers, 1 uterus cancer). The normal tissue paneltested was the same as in FIGS. 1E-1K. FIG. 1Y) Gene symbol(s): EMC10,Peptide: SLVESHLSDQLTL (SEQ ID NO.: 463). Tissues from left to right: 1primary culture, 32 cancer tissues (1 bile duct cancer, 2 brain cancers,2 breast cancers, 2 head and neck cancers, 3 leukocytic leukemiacancers, 1 liver cancer, 8 lung cancers, 3 lymph node cancers, 5 ovariancancers, 2 skin cancers, 2 urinary bladder cancers, 1 uterus cancer).The normal tissue panel tested was the same as in FIGS. 1E-1K. FIG. 1Z)Gene symbol(s): ZYG11A, Peptide: VLIANLEKL (SEQ ID NO.: 466). Tissuesfrom left to right: 5 cell lines, 17 cancer tissues (3 breast cancers, 2esophageal cancers, 1 liver cancer, 2 lung cancers, 5 lymph nodecancers, 3 ovarian cancers, 1 urinary bladder cancer). The normal tissuepanel tested was the same as in FIGS. 1E-1K. FIG. 1AA) Gene symbol(s):CEP192, Peptide: SLFGNSGILENV (SEQ ID NO.: 479). Tissues from left toright: 7 cell lines, 1 normal tissue (1 spleen), 33 cancer tissues (1breast cancer, 1 colon cancer, 1 esophageal cancer, 1 head and neckcancer, 1 leukocytic leukemia cancer, 3 liver cancers, 10 lung cancers,1 lymph node cancer, 1 myeloid cell cancer, 7 ovarian cancers, 2 skincancers, 3 urinary bladder cancers, 1 uterus cancer). The normal tissuepanel tested was the same as in FIGS. 1E-1K. FIG. 1AB) Gene symbol(s):CCNA1, Peptide: SLSEIVPCL (SEQ ID NO.: 512). Tissues from left to right:9 cancer tissues (1 head and neck cancer, 2 lung cancers, 1 myeloid cellcancer, 3 ovarian cancers, 2 uterus cancers). The normal tissue paneltested was the same as in FIGS. 1E-1K. FIG. 1AC) Gene symbol(s): GNB1,Peptide: ALWDIETGQQTTT (SEQ ID NO.: 560), Tissues from left to right: 5cell lines and primary cultures, 26 cancer tissues (1 brain cancer, 1esophageal cancer, 1 esophageal and stomach cancer, 1 gallbladdercancer, 2 head and neck cancers, 1 leukocytic leukemia cancer, 1 livercancer, 5 lung cancers, 6 lymph node cancers, 3 ovarian cancers, 1prostate cancer, 1 skin cancer, 1 urinary bladder cancer, 1 uteruscancer). The normal tissue panel tested was the same as in FIGS. 1E-1K.FIG. 1AD) Gene symbol(s): KLHL14, Peptide: VMNDRLYAI (SEQ ID NO.: 587),Tissues from left to right: 5 normal tissues (1 pancreas, 3 spleens, 1thyroid gland), 38 cancer tissues (14 leukocytic leukemia cancers, 10lymph node cancers, 9 ovarian cancers, 1 prostate cancer, 4 uteruscancers). The normal tissue panel tested was the same as in FIGS. 1E-1K.FIG. 1AE) Gene symbol(s): URB1, Peptide: KLLNKIYEA (SEQ ID NO.: 620),Tissues from left to right: 3 cell lines and primary cultures, 2 normaltissues (1 lung, 1 uterus), 27 cancer tissues (5 brain cancers, 2 breastcancers, 2 esophageal cancers, 5 lung cancers, 1 lymph node cancer, 1myeloid cell cancer, 5 ovarian cancers, 3 prostate cancers, 1 rectumcancer, 1 urinary bladder cancer, 1 uterus cancer). The normal tissuepanel tested was the same as in FIGS. 1E-1K.

FIGS. 2A to 2D show exemplary expression profiles of source genes of thepresent invention that are highly over-expressed or exclusivelyexpressed in ovarian cancer in a panel of normal tissues (white bars)and 20 ovarian cancer samples (black bars). Tissues from left to right:7 arteries, 1 brain, 1 heart, 2 livers, 2 lungs, 2 veins, 1 adiposetissue, 1 adrenal gland, 4 bone marrows, 1 colon, 2 esophagi, 2gallbladders, 1 kidney, 6 lymph nodes, 1 pancreas, 1 pituitary gland, 1rectum, 1 skeletal muscle, 1 skin, 1 small intestine, 1 spleen, 1stomach, 1 thymus, 1 thyroid gland, 5 tracheae, 1 urinary bladder, 1breast, 3 ovaries, 3 placentae, 1 prostate, 1 testis, 1 uterus. FIG. 2A)CT45A1, CT45A3, CT45A5, CT45A6, CT45A2, RP11-342L5.1, FIG. 2B) CLDN16;FIG. 2C) ESR1; FIG. 2D) IDO1.

FIGS. 3A to 3F show exemplary immunogenicity data: flow cytometryresults after peptide-specific multimer staining. CD8+ T cells wereprimed using artificial APCs coated with anti-CD28 mAb and HLA-A*02 incomplex with SeqID No 662 (FIG. 3A, left panel), SeqID No 663 (FIG. 3B,left panel), SeqID No 11 peptide (FIG. 3C, left panel), SeqID No 198peptide (FIG. 3D, left panel), SeqID No 587 peptide (FIG. 3E, leftpanel) and SeqID No 427 peptide (FIG. 3F, left panel), respectively.After three cycles of stimulation, the detection of peptide-reactivecells was performed by 2D multimer staining with A*02/SeqID No 662 (FIG.3A), A*02/SeqID No 663 (FIG. 3B), A*02/SeqID No 11 (FIG. 3C), A*02/SeqIDNo 198 (FIG. 3D), A*02/SeqID No 587 (FIG. 3E) or A*02/SeqID No 427 (FIG.3F). Right panels (FIGS. 3A, 3B, 3C, 3D, 3E, and 3F) show controlstaining of cells stimulated with irrelevant A*02/peptide complexes.Viable singlet cells were gated for CD8+ lymphocytes. Boolean gateshelped excluding false-positive events detected with multimers specificfor different peptides. Frequencies of specific multimer+ cells amongCD8+ lymphocytes are indicated.

EXAMPLES Example 1

Identification and Quantitation of Tumor Associated Peptides Presentedon the Cell Surface

Tissue Samples

Patients' tumor tissues were obtained from Asterand (Detroit, USA andRoyston, Herts, UK); Val d'Hebron University Hospital (Barcelona);ProteoGenex Inc., (Culver City, Calif., USA); Stanford Cancer Center(Stanford, Calif., USA); University Hospital of Tobingen. Normal(healthy) tissues were obtained from Asterand (Detroit, USA and Royston,Herts, UK); Bio-Options Inc., CA, USA; BioServe, Beltsville, Md., USA;Capital BioScience Inc., Rockville, Md., USA; Geneticist Inc., Glendale,Calif., USA; University Hospital of Geneva; University Hospital ofHeidelberg; University Hospital Munich; ProteoGenex Inc., Culver City,Calif., USA; University Hospital of TObingen, Kyoto PrecaturalUniversity if Medicine (KPUM). Written informed consents of all patientshad been given before surgery or autopsy. Tissues were shock-frozenimmediately after excision and stored until isolation of TUMAPs at −70°C. or below.

Isolation of HLA Peptides from Tissue Samples

HLA peptide pools from shock-frozen tissue samples were obtained byimmune precipitation from solid tissues according to a slightly modifiedprotocol (Falk et al., 1991; Seeger et al., 1999) using theHLA-A*02-specific antibody BB7.2, the HLA-A, -B, C-specific antibodyW6/32, CNBr-activated sepharose, acid treatment, and ultrafiltration.

Mass Spectrometry Analyses

The HLA peptide pools as obtained were separated according to theirhydrophobicity by reversed-phase chromatography (nanoAcquity UPLCsystem, Waters) and the eluting peptides were analyzed in LTQ-velos andfusion hybrid mass spectrometers (ThermoElectron) equipped with an ESIsource. Peptide pools were loaded directly onto the analyticalfused-silica micro-capillary column (75 μm i.d.×250 mm) packed with 1.7μm C18 reversed-phase material (Waters) applying a flow rate of 400 nLper minute. Subsequently, the peptides were separated using a two-step180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nLper minute. The gradient was composed of Solvent A (0.1% formic acid inwater) and solvent B (0.1% formic acid in acetonitrile). A gold coatedglass capillary (PicoTip, New Objective) was used for introduction intothe nanoESI source. The LTQ-Orbitrap mass spectrometers were operated inthe data-dependent mode using a TOP5 strategy. In brief, a scan cyclewas initiated with a full scan of high mass accuracy in the Orbitrap(R=30 000), which was followed by MS/MS scans also in the Orbitrap(R=7500) on the 5 most abundant precursor ions with dynamic exclusion ofpreviously selected ions. Tandem mass spectra were interpreted bySEQUEST and additional manual control. The identified peptide sequencewas assured by comparison of the generated natural peptide fragmentationpattern with the fragmentation pattern of a synthetic sequence-identicalreference peptide.

Label-free relative LC-MS quantitation was performed by ion countingi.e. by extraction and analysis of LC-MS features (Mueller et al.,2007). The method assumes that the peptide's LC-MS signal areacorrelates with its abundance in the sample. Extracted features werefurther processed by charge state deconvolution and retention timealignment (Mueller et al., 2008; Sturm et al., 2008). Finally, all LC-MSfeatures were cross-referenced with the sequence identification resultsto combine quantitative data of different samples and tissues to peptidepresentation profiles. The quantitative data were normalized in atwo-tier fashion according to central tendency to account for variationwithin technical and biological replicates. Thus each identified peptidecan be associated with quantitative data allowing relativequantification between samples and tissues. In addition, allquantitative data acquired for peptide candidates was inspected manuallyto assure data consistency and to verify the accuracy of the automatedanalysis. For each peptide a presentation profile was calculated showingthe mean sample presentation as well as replicate variations. Theprofiles juxtapose ovarian cancer samples to a baseline of normal tissuesamples. Presentation profiles of exemplary over-presented peptides areshown in FIGS. 1A-1AE. Presentation scores for exemplary peptides areshown in Table 9.

TABLE 9 Presentation scores. The table lists peptidesthat are very highly over-presented on tumorscompared to a panel of normal tissues (+++),highly over-presented on tumors compared toa panel of normal tissues (++) or over-presented on tumors compared to a panel ofnormal tissues (+). The panel of normal tissuesconsisted of: adipose tissue, adrenal gland,artery, vein, bone marrow, brain, central andperipheral nerve, colon, rectum, small intestineincl. duodenum, esophagus, gallbladder, heart,kidney, liver, lung, lymph node, mononuclearwhite blood cells, pancreas, peritoneum,pituitary, pleura, salivary gland, skeletalmuscle, skin, spleen, stomach, thymus, thyroidgland, trachea, ureter, urinary bladder. SEQ ID Peptide No. SequencePresentation 1 SLMEPPAVLLL +++ 2 SLLEADPFL +++ 3 SLASKLTTL +++ 4GIMEHITKI +++ 5 HLTEVYPEL +++ 6 VLVSDGVHSV +++ 7 SLVGLLLYL +++ 8FTLGNVVGMYL +++ 9 GAAKDLPGV ++ 10 FLATFPLAAV +++ 11 KIFEMLEGV +++ 12SLWPDPMEV +++ 13 YLMDESLNL +++ 14 AAYGGLNEKSFV +++ 15 VLLTFKIFL +++ 16VLFQGQASL ++ 17 GLLPGDRLVSV +++ 18 YLVAKLVEV +++ 20 RMIEYFIDV +++ 21VLDELDMEL +++ 23 VLLDDIFAQL +++ 24 SLSDGLEEV ++ 25 FLPDEPYIKV +++ 26ALLELAEEL +++ 27 ILADIVISA + 28 QLLDETSAITL +++ 29 KMLGIPISNILMV ++ 30LILDWVPYI ++ 31 YLAPELFVNV +++ 32 KLDDLTQDLTV +++ 33 VLLSLLEKV ++ 34ILVEADSLWVV +++ 35 KINDTIYEV +++ 36 YVLEDLEVTV +++ 37 LLWDVVTGQSV +++ 38FLLEDDIHVS +++ 39 SVAPNLPAV +++ 40 TLLVKVFSV +++ 41 SLMPHIPGL +++ 42VLLQKIVSA +++ 43 VLSSLEINI + 44 ILDPISSGFLL +++ 45 SLWQDIPDV +++ 46ILTEENIHL +++ 47 ILLSVPLLVV +++ 48 ALAELYEDEV +++ 50 SLSELEALM +++ 51LLPDLEFYV +++ 52 FLLAHGLGFLL +++ 53 KMIETDILQKV +++ 54 SLLEQGKEPWMV +++55 SLLDLETLSL +++ 56 KLYEGIPVLL +++ 57 TLAELQPPVQL +++ 58 FLDTLKDLI ++59 IMEDIILTL +++ 60 SLTIDGIYYV +++ 61 FLQGYQLHL +++ 62 VLLDVSAGQLLM +++63 YLLPSGGSVTL +++ 64 YAAPGGLIGV + 65 LKVNQGLESL +++ 67 TLLAEALVTV +++68 SLMELPRGLFL +++ 69 FQLDPSSGVLVTV +++ 70 GLLDYPVGV +++ 71 GILARIASV+++ 72 SLLELDGINL +++ 73 NIFDLQIYV +++ 74 ALLDPEVLSIFV +++ 75 GLLEVMVNL+++ 76 ILIDSIYKV +++ 77 ILVEADGAWVV +++ 78 SLFSSLEPQIQPV +++ 79SLFIGEKAVLL ++ 81 FLFSQLQYL +++ 82 FLSSVTYNL +++ 83 ILAPTVMMI +++ 84VTFGEKLLGV +++ 86 NLIGKIENV + 87 ALPEAPAPLLPHIT +++ 88 FLLVGDLMAV +++ 89YILPTETIYV +++ 90 TLLQIIETV +++ 91 IMQDFPAEIFL +++ 92 YLIPFTGIVGL +++ 93LLQAIKLYL +++ 94 YLIDIKTIAI +++ 96 YIFTDNPAAV +++ 97 SLINGSFLV +++ 98LIIDQADIYL +++ 99 ALVSKGLATV +++ 100 YLLSTNAQL +++ 101 ILVGGGALATV +++102 YLFESEGLVL +++ 103 TLAEEVVAL +++ 105 LLLEHSFEI ++ 106 LLYDAVHIVSV+++ 107 FLQPVDDTQHL +++ 108 ALFPGVALLLA +++ 109 IILSILEQA +++ 110FLSQVDFEL +++ 111 YVWGFYPAEV +++ 112 FLITSNNQL +++ 113 GLLPTPLFGV +++114 SLVGEPILQNV +++ 116 YHIDEEVGF +++ 117 ILPDGEDFLAV +++ 118 KLIDNNINV+++ 119 FLYIGDIVSL ++ 120 ALLGIPLTLV +++ 122 FLLAEDDIYL +++ 123NLWDLTDASVV +++ 124 ALYETELADA +++ 125 VQIHQVAQV +++ 126 VLAYFLPEA + 127KIGDEPPKV ++ 129 GLLDGGVDILL ++ 130 FLWNGEDSALL +++ 131 FVPPVTVFPSL +++132 LLVEQPPLAGV +++ 134 YLQELIFSV +++ 135 ALSEVDFQL +++ 136 YLADPSNLFVV+++ 137 TLVLTLPTV +++ 138 YQYPRAILSV +++ 139 SVMEVNSGIYRV +++ 141YLDFSNNRL +++ 142 FLFATPVFI +++ 143 LLLDITPEI +++ 144 YIMEPSIFNTL ++ 145FLATSGTLAGI +++ 146 SLATAGDGLIEL +++ 147 SLLEAVSFL + 148 ALNPEIVSV +++149 NLLELFVQL +++ 150 RLWEEGEELEL +++ 151 KILQQLVTL +++ 152 ILFEDIFDV+++ 153 FLIANVLYL +++ 155 RVANLHFPSV + 156 AISQGITLPSL +++ 157 SLNDEVPEV+++ 158 KLFDVDEDGYI +++ 159 GLVGNPLPSV +++ 160 FLFDEEIEQI ++ 161ALLEGVNTV +++ 162 YQQAQVPSV +++ 163 ALDEMGDLLQL +++ 164 ALLPQPKNLTV +++165 SLLDEIRAV +++ 166 YLNHLEPPV +++ 167 KVLEVTEEFGV ++ 168 KILDADIQL +++169 NLPEYLPFV +++ 170 RLQETLSAA +++ 171 LLLPLQILL +++ 172 VLYSYTIITV +++173 LLDSASAGLYL +++ 174 ALAQYLITA ++ 175 YLFENISQL +++ 176 YLMEGSYNKVFL+++ 177 YLLPEEYTSTL +++ 178 ALTEIAFVV + 179 KVLNELYTV +++ 180FQIDPHSGLVTV +++ 181 LLWAGTAFQV +++ 182 MLLEAPGIFL +++ 183 FGLDLVTEL ++184 YLMDINGKMWL +++ 185 FLIDDKGYTL +++ 186 TLFFQQNAL + 187 RQISIRGIVGV+++ 188 GLFPVTPEAV + 189 ALQRKLPYV +++ 190 FLSSLTETI +++ 191 LLQEGQALEYV+++ 192 KMLDGASFTL +++ 193 QLLDADGFLNV +++ 194 ALPLFVITV +++ 196YLYSVEIKL +++ 197 ALGPEGGRV ++ 198 KTINKVPTV +++ 199 ALQDVPLSSV +++ 200LLFGSVQEV +++ 201 RLVDYLEGI +++ 202 ALLDQQGSRWTL +++ 203 VLLEDAHSHTL +++204 KIAENVEEV +++ 205 SLYPGTETMGL +++ 206 VLQEGKLQKLAQL +++ 208KISPVTFSV +++ 209 KLIESKHEV +++ 210 LLLNAVLTV ++ 211 LLWPGAALL +++ 212ALWDQDNLSV +++ 213 VTAAYMDTVSL ++ 215 QLINHLHAV +++ 216 NLWEDPYYL +++217 ALIHPVSTV +++ 218 SALEELVNV +++ 219 KLSDIGITV +++ 220 LLQKFVPEI +++221 ALYEEGLLL +++ 222 NLIENVQRL ++ 223 ALLENIALYL +++ 224 TLIDAQWVL +++225 SLLKVLPAL +++ 226 MLYVVPIYL +++ 227 ALMNTLLYL +++ 228 AMQEYIAVV +229 RLPGPLGTV ++ 230 ILVDWLVEV +++ 231 FLSPQQPPLLL +++ 232 ALLEAQDVELYL+++ 233 VLSETLYEL ++ 234 ALMEDTGRQML +++ 235 YLNDLHEVLL +++ 236GLLEAKVSL +++ 237 ALLEASGTLLL +++ 238 YLISFQTHI +++ 239 AAFAGKLLSV +++240 ILLEQAFYL +++ 241 SLVEVNPAYSV +++ 242 AIAYILQGV +++ 243 LLLNELPSV ++244 SLFGGTEITI +++ 245 SMIDDLLGV +++ 246 LLWEVVSQL +++ 247 VLLPNDLLEKV+++ 248 FLFPNQYVDV + 249 LLDGFLVNV +++ 251 ALYTGFSILV +++ 252 LLIGTDVSL+++ 253 GLDAATATV +++ 254 TLLAFIMEL +++ 255 VLASYNLTV +++ 256FLPPEHTIVYI +++ 257 SIFSAFLSV +++ 259 TLMRQLQQV ++ 261 YVLEFLEEI + 263LLVSNLDFGV +++ 267 ALQDFLLSV +++ 271 LVYPLELYPA ++ 274 SLLFSLFEA + 275YLVYILNEL + 277 LLPPLESLATV + 278 QLLDVVLTI + 279 ALWGGTQPLL ++ 280VLPDPEVLEAV + 281 ILRESTEEL + 282 LLADVVPTT + 285 QLLHVGVTV + 288NLINEINGV +++ 289 VLLEIEDLQV + 292 LLWEAGSEA + 296 FMEGAIIYV ++ 298VMITKLVEV ++ 303 AILPQLFMV + 307 ALPVSLPQI + 308 SQYSGQLHEV + 311RLYTGMHTV + 315 YLQDVVEQA ++ 318 GLINTGVLSV + 319 SLEPQIQPV + 320KMFEFVEPLL + 321 GLFEDVTQPGILL ++ 322 TLMTSLPAL ++ 323 IQIGEETVITV + 325FIMPATVADATAV +++ 327 GLAPFTEGISFV ++ 328 ALNDQVFEI + 331 KVDTVWVNV +332 YLISELEAA + 333 FLPDANSSV ++ 334 TLTKVLVAL + 338 SVLEDPVHAV + 341SQIALNEKLVNL + 342 HIYDKVMTV + 343 SLLEVNEESTV + 345 VIWKALIHL ++ 346LLDSKVPSV ++ 348 ILLDVKTRL +++ 351 SLIPNLRNV +++ 352 SLLELLHIYV + 356KLLGKLPEL ++ 357 SMHDLVLQV ++ 358 ALDEYTSEL + 359 YLLPESVDL + 360ALDJGASLLHL + 363 KVLDVSDLESV ++ 368 ILLEEVSPEL + 370 SLLQDLVSV + 372TMLLNIPLV +++ 373 SLLEDKGLAEV + 375 SLTETIEGV +++ 379 IMEGTLTRV + 382ALQNYIKEA + 384 ILFANPNIFV + 385 SLLEQGLVEA + 386 ILFRYPLTI ++ 390ALFMKQIYL ++ 394 LLAVIGGLVYL + 395 ALALGGIAVV ++ 396 ALLPDLPAL ++ 397YLFGERLLEC + 398 KLLEEDGTIITL + 399 YLFEPLYHV +++ 401 ILLDDTGLAYI + 403KLYDRILRV ++ 404 AIDIJGRDPAV + 406 SVQGEDLYLV ++ 410 VLSDVIPJI ++ 411LLAHLSPEL + 413 TLLEKVEGC ++ 414 YVDDIFLRV + 415 LLDKVYSSV + 418ALAELENIEV + 419 GQYEGKVSSV + 420 FMYDTPQEV ++ 421 RLPETLPSL ++ 423GLDGPPPTV +++ 424 TLLDALYEI + 425 FLYEKSSQV + 427 ALLPLSPYL +++ 428KLGHTDILVGV ++ 429 GLVNDLARV + 430 HLYSSIEHLTT + 431 SLVNVVPKL + 432TLIEESAKV +++ 433 AMLNEPWAV +++ 434 KVSNSGITRV +++ 435 WLMPVIPAL +++ 436HLAEVSAEV +++ 437 SMAPGLVIQAV +++ 438 KLLPLAGLYL +++ 439 YLLQEIYGI +++440 ALADGVTMQV +++ 441 ALLENPKMEL +++ 442 GLLGGGGVLGV +++ 443GLWEIENNPTV ++ 444 GLLRDEALAEV +++ 446 QLIPALAKV +++ 447 QLVPALAKV +++448 NLLETKLQL ++ 450 FMIDASVHPTL +++ 451 LLLLDTVTMQV +++ 454 KLPPPPPQA+++ 455 SLLKEPQKVQL + 456 LLIGHLERV ++ 457 SLLPGNLVEKV +++ 458 SLIDKLYNI+++ 459 ALITEVVRL +++ 460 AMLEKNYKL +++ 461 VMFRTPLASV +++ 462 KLAKQPETV+++ 463 SLVESHLSDQLTL +++ 464 ALNDCIYSV +++ 465 QLCDLNAEL +++ 466VLIANLEKL +++ 468 YLRSVGDGETV + 470 MLQDSIHVV +++ 471 YLYNNMIAKI +++ 472KLLEVSDDPQV ++ 473 AMATESILHFA +++ 474 YLDPALELGPRNV + 475 LLLNEEALAQI+++ 476 ALMERTGYSMV +++ 477 ALLPASGQIAL +++ 478 YLLHEKLNL +++ 479SLFGNSGILENV + 480 ALLEDSCHYL + 481 GLIEDYEALL +++ 482 SLAPAGIADA +++483 ALTDIVSQV + 486 AVMESIQGV ++ 487 LLINSVFHV + 488 FLAEDPKVTL + 489KMWEELPEVV +++ 490 FLLQHVQEL +++ 491 GLNDRSDAV +++ 492 SLFDGFADGLGV +++494 ALQPEPIKV +++ 495 FIFSEKPVFV + 496 FLVEKQPPQV +++ 497 GLLEKLTAI +498 KLWTGGLDNTV + 499 KIFDIDEAEEGV +++ 500 SLMEDQVLQL + 501 LLDPNVKSIFV++ 502 RLLAQVPGL +++ 503 SLNHFTHSV + 504 GLSDGNPSL +++ 505 SLAPGDVVRQV+++ 506 KLLGKVETA +++ 507 KLIDDQDISISL + 508 ILAQEQLVVGV +++ 509FLFDTKPLIV +++ 510 KLYSVVSQL +++ 511 FLDPYCSASV +++ 512 SLSEIVPCL +++513 SLWPSPEQL +++ 514 ILVDWLVQV +++ 515 LLQELVLFL +++ 516 AVGPASILKEV+++ 517 LLMPIPEGLTL + 518 KLNAEVACV +++ 519 GLLHLTLLL +++ 520 LAVHPSGVAL++ 521 MLLTKLPTI ++ 522 TLWYRSPEV +++ 523 YQIPRTFTL + 525 VLLEAGEGLVTI +526 RLAEVGQYEQV + 527 FLLEPGNLEV +++ 528 SVAEGRALMSV + 529 LLADELITV ++530 VMYADIGGMDI + 531 YTLPIASSIRL + 538 LLLAHIIAL ++ 539 ALFDAQAQV ++540 ALIPETTTLTV ++ 541 SMLEPVPEL + 543 GLLPTPITQQASL + 545 LLADLLHNV +546 VMIAGKVAVV + 550 FLYDEIEAEVNL + 551 KLYESLLPFA ++ 554 LLMPSSEDLLL ++557 KLYDDMIRL + 558 GLLENIPRV ++ 560 ALWDIETGQQTTT + 561 YLQLTQSEL +++563 WLLPYNGVTV + 564 TVTNAVVTV ++ 565 ALQETPTSV ++ 566 VIADGGIQNV ++ 568TLYDIAHTPGV ++ 570 ALANQIPTV + 574 YLLQEPPRTV + 575 YLISQVEGHQV + 576ILLNNSGQIKL ++ 579 NLMEMVAQL ++ 586 KLKPGDLVGV + 588 SLLPLSHLV + 589KLYPQLPAEI + 590 SLIEKLWQT + 591 SMAELDIKL ++ 593 GLPRFGIEMV + 595VLLSIYPRV + 597 KLLEGQVIQL + 599 YLLNDASLISV ++ 601 SAFPFPVTV + 603FLIEPEHVNTV + 606 ALWETEVYI ++ 610 LLAPTPYIIGV + 613 RLLPPGAVVAV ++ 618VLFDSESIGIYV + 619 ALQDRVPLA + 625 VVLEGASLETV + 626 LLMATILHL ++ 627KLLETELLQEI + 629 HLLNESPML ++ 630 LLSHVIVAL + 631 FLDVFLPRV + 632YLIPDIDLKL ++ 634 VVAEFVPLI + 637 SIYGGFLLGV ++ 638 KLIQESPTV + 639SLFQNCFEL + 640 YLFSEALNAA +

Example 2

Expression Profiling of Genes Encoding the Peptides of the Invention

Over-presentation or specific presentation of a peptide on tumor cellscompared to normal cells is sufficient for its usefulness inimmunotherapy, and some peptides are tumor-specific despite their sourceprotein occurring also in normal tissues. Still, mRNA expressionprofiling adds an additional level of safety in selection of peptidetargets for immunotherapies. Especially for therapeutic options withhigh safety risks, such as affinity-matured TCRs, the ideal targetpeptide will be derived from a protein that is unique to the tumor andnot found on normal tissues.

RNA Sources and Preparation

Surgically removed tissue specimens were provided as indicated above(see Example 1) after written informed consent had been obtained fromeach patient. Tumor tissue specimens were snap-frozen immediately aftersurgery and later homogenized with mortar and pestle under liquidnitrogen. Total RNA was prepared from these samples using TRI Reagent(Ambion, Darmstadt, Germany) followed by a cleanup with RNeasy (QIAGEN,Hilden, Germany); both methods were performed according to themanufacturer's protocol.

Total RNA from healthy human tissues for RNASeq experiments was obtainedfrom: Asterand, Detroit, USA and Royston, Herts, UK; ProteoGenex Inc.Culver City, Calif., USA, Geneticist Inc., Glendale, Calif., USA,Istituto Nazionale Tumori “Pascale”, Molecular Biology and ViralOncology Unit (IRCCS), Naples, Italy, University Hospital of Heidelberg,Germany, BioCat GmbH, Heidelberg, Germany.

Quality and quantity of all RNA samples were assessed on an Agilent 2100Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 PicoLabChip Kit (Agilent).

RNAseq Experiments

Gene expression analysis of—tumor and normal tissue RNA samples wasperformed by next generation sequencing (RNAseq) by CeGaT (TObingen,Germany). Briefly, sequencing libraries are prepared using the IlluminaHiSeq v4 reagent kit according to the provider's protocol (IlluminaInc., San Diego, Calif., USA), which includes RNA fragmentation, cDNAconversion and addition of sequencing adaptors. Libraries derived frommultiple samples are mixed equimolar and sequenced on the Illumina HiSeq2500 sequencer according to the manufacturer's instructions, generating50 bp single end reads. Processed reads are mapped to the human genome(GRCh38) using the STAR software. Expression data are provided ontranscript level as RPKM (Reads Per Kilobase per Million mapped reads,generated by the software Cufflinks) and on exon level (total reads,generated by the software Bedtools), based on annotations of the ensemblsequence database (Ensembl77). Exon reads are normalized for exon lengthand alignment size to obtain RPKM values.

Exemplary expression profiles of source genes of the present inventionthat are highly over-expressed or exclusively expressed in ovariancancer are shown in FIGS. 2A to 2D. Expression scores for furtherexemplary genes are shown in Table 10.

TABLE 10 Expression scores. The table lists peptides from genes that are very highlyover-expressed in tumors compared to a panel of normal tissues (+++), highly over-expressed in tumors compared to a panel of normal tissues (++) or over-expressed intumors compared to a panel of normal tissues (+). The baseline for this score wascalculated from measurements of the following normal tissues: adipose tissue, adrenalgland, artery, bone marrow, brain, colon, esophagus, gallbladders, heart, kidney, liver,lung, lymph node, pancreas, pituitary, rectum, skeletal muscle, skin, small intestine,spleen, stomach, thymus, thyroid gland, trachea, urinary bladder, vein.SEQ ID Gene No. Gene Name Sequence Expression 1 CCNA1 SLMEPPAVLLL +++ 2CCNA1 SLLEADPFL +++ 3 MUC16 SLASKLTTL +++ 4 MUC16 GIMEHITKI +++ 5 MUC16HLTEVYPEL +++ 11 CT45A1, CT45A3, CT45A5,  KIFEMLEGV +++CT45A6, CT45A2, RP11-342L5.1 15 GPR64 VLLTFKIFL +++ 21 IFI30 VLDELDMEL +25 CLDN16 FLPDEPYIKV +++ 41 TDRD9 SLMPHIPGL + 42 TDRD9 VLLQKIVSA + 45ARHGEF19 SLWQDIPDV ++ 67 MUC20 TLLAEALVTV + 69 FAT2 FQLDPSSGVLVTV +++ 72VWDE SLLELDGINL +++ 81 NUP205 FLFSQLQYL + 101 GPD2 ILVGGGALATV + 102GAS2L3 YLFESEGLVL ++ 113 BPIFB3 GLLPTPLFGV +++ 114 BPIFB3 SLVGEPILQNV+++ 115 AQP5 AIAGAGILYGV ++ 116 IDO1 YHIDEEVGF +++ 118 ITGB8 KLIDNNINV++ 126 MCM2 VLAYFLPEA + 171 KLK7 LLLPLQILL +++ 173 KIF15 LLDSASAGLYL +++181 KIAA1324 LLWAGTAFQV + 183 RNF213 FGLDLVTEL ++ 184 RNF213 YLMDINGKMWL++ 193 CLSPN QLLDADGFLNV +++ 194 SLC28A3 ALPLFVITV ++ 195 MROH6GLFADLLPRL + 197 SOX17 ALGPEGGRV ++ 210 UNG LLLNAVLTV + 215 BHLHE41QLINHLHAV ++ 230 CCNA2, CCNA1, CCNB3 ILVDWLVEV +++ 233 TIMELESSVLSETLYEL ++ 235 CCNE1 YLNDLHEVLL ++ 239 RSAD2 AAFAGKLLSV + 244 PKHD1L1SLFGGTEITI +++ 258 NCAPD2 ELAERVPAI ++ 259 C20orf96 TLMRQLQQV + 266 ESR1KITDTLIHL +++ 310 GGT6 FLVDTPLARA + 311 SGPP2 RLYTGMHTV + 317 FAT2SLAALVVHV ++ 327 APOL2 GLAPFTEGISFV ++ 335 IGHG1, IGHG4, IGHG3,YSLSSVVTV +++ IGHG2 339 HDGF GLWEIENNPTVKA + 342 VWA2 HIYDKVMTV ++ 350LAMA5 ALLDVTHSELTV ++ 371 RNF213 FLQAHLHTA ++ 372 RNF213 TMLLNIPLV ++387 ALMS1 ALFQATAEV + 393 EPPK1 GLLDTQTSQVLTA ++ 395 ARID5B ALALGGIAVV +408 KLHL14 VLDDSIYLV +++ 409 KLHL14 LLDAMNYHL +++ 421 SCNN1A RLPETLPSL+++ 423 TNFAIP2 GLDGPPPTV ++ 426 NCAPD2 RLADKSVLV + 427 VTCN1 ALLPLSPYL+++ 432 ABCC4 TLIEESAKV + 442 BPIFB4 GLLGGGGVLGV ++ 443 HDGF, HDGFL1GLWEIENNPTV + 446 EYA4, EYA1, EYA2 QLIPALAKV +++ 456 NUP205 LLIGHLERV +465 KIFC1 QLCDLNAEL ++ 466 ZYG11A VLIANLEKL ++ 467 MX2 FLAKDFNFL ++ 484KIF15 SLIEKVTQL +++ 494 SORL1 ALQPEPIKV ++ 495 SORL1 FIFSEKPVFV + 509CANX FLFDTKPLIV + 512 CCNA1 SLSEIVPCL +++ 519 NFE2L3 GLLHLTLLL +++ 523GAB2 YQIPRTFTL +++ 551 NCAPD3 KLYESLLPFA + 579 CHD7 NLMEMVAQL ++ 580ASUN LLMENAERV + 587 KLHL14 VMNDRLYAI +++ 588 RNF213 SLLPLSHLV + 595TAP1 VLLSIYPRV ++ 602 ERMP1 YLLEQIKLIEV ++ 609 HELZ2 ALWKQLLEL + 614UBE2L6 LLLPDQPPYHL ++ 616 TRIP13 VLIDEVESL ++ 629 NUP205 HLLNESPML + 631PRKDC FLDVFLPRV + 632 SMARCC1 YLIPDIDLKL +

Example 3

In Vitro Immunoqenicity for MHC Class I Presented Peptides

In order to obtain information regarding the immunogenicity of theTUMAPs of the present invention, the inventors performed investigationsusing an in vitro T-cell priming assay based on repeated stimulations ofCD8+ T cells with artificial antigen presenting cells (aAPCs) loadedwith peptide/MHC complexes and anti-CD28 antibody. This way theinventors could show immunogenicity for 22 HLA-A*0201 restricted TUMAPsof the invention so far, demonstrating that these peptides are T-cellepitopes against which CD8+ precursor T cells exist in humans (Table11).

In Vitro Priming of CD8+ T Cells

In order to perform in vitro stimulations by artificial antigenpresenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28antibody, the inventors first isolated CD8+ T cells from fresh HLA-A*02leukapheresis products via positive selection using CD8 microbeads(Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtainedfrom the University clinics Mannheim, Germany, after informed consent.

PBMCs and isolated CD8+ lymphocytes were incubated in T-cell medium(TCM) until use consisting of RPMI-Glutamax (Invitrogen, Karlsruhe,Germany) supplemented with 10% heat inactivated human AB serum(PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100 μg/mlStreptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro,Oberdorla, Germany), 20 μg/ml Gentamycin (Cambrex). 2.5 ng/ml IL-7(PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma,Nornberg, Germany) were also added to the TCM at this step.

Generation of pMHC/anti-CD28 coated beads, T-cell stimulations andreadout was performed in a highly defined in vitro system using fourdifferent pMHC molecules per stimulation condition and 8 different pMHCmolecules per readout condition.

The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung etal., 1987) was chemically biotinylated usingSulfo-N-hydroxysuccinimidobiotin as recommended by the manufacturer(Perbio, Bonn, Germany). Beads used were 5.6 μm diameter streptavidincoated polystyrene particles (Bangs Laboratories, Illinois, USA).

pMHC used for positive and negative control stimulations wereA*0201/MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 664) from modifiedMelan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5, SEQ ID NO.665), respectively.

800.000 beads/200 μl were coated in 96-well plates in the presence of4×12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 wereadded subsequently in a volume of 200 μl. Stimulations were initiated in96-well plates by co-incubating 1×10⁶ CD8+ T cells with 2×10⁵ washedcoated beads in 200 μl TCM supplemented with 5 ng/ml IL-12 (PromoCell)for 3 days at 37° C. Half of the medium was then exchanged by fresh TCMsupplemented with 80 U/ml IL-2 and incubating was continued for 4 daysat 37° C. This stimulation cycle was performed for a total of threetimes. For the pMHC multimer readout using 8 different pMHC moleculesper condition, a two-dimensional combinatorial coding approach was usedas previously described (Andersen et al., 2012) with minor modificationsencompassing coupling to 5 different fluorochromes. Finally, multimericanalyses were performed by staining the cells with Live/dead near IR dye(Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD,Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BDLSRII SORP cytometer equipped with appropriate lasers and filters wasused. Peptide specific cells were calculated as percentage of total CD8+cells. Evaluation of multimeric analysis was done using the FlowJosoftware (Tree Star, Oregon, USA). In vitro priming of specificmultimer+CD8+ lymphocytes was detected by comparing to negative controlstimulations. Immunogenicity for a given antigen was detected if atleast one evaluable in vitro stimulated well of one healthy donor wasfound to contain a specific CD8+ T-cell line after in vitro stimulation(i.e. this well contained at least 1% of specific multimer+ among CD8+T-cells and the percentage of specific multimer+ cells was at least 10×the median of the negative control stimulations).

In Vitro Immunogenicity for Ovarian Cancer Peptides

For tested HLA class I peptides, in vitro immunogenicity could bedemonstrated by generation of peptide specific T-cell lines. Exemplaryflow cytometry results after TUMAP-specific multimer staining for twopeptides of the invention are shown in FIGS. 3A to 3F together withcorresponding negative controls. Results for six peptides from theinvention are summarized in Table 11A and B.

TABLE 11Ain vitro immunogenicity of HLA class I peptides of the invention. Exemplary results of in vitro immunogenicity experiments conducted by the applicant for the peptides of the invention. <20% = +; 20%-49% = ++; 50%-69% = +++; >= 70% = ++++ SEQ ID NO: Sequencewells donors 283 ALYIGDGYVIHLA + +++ 648 LLWGNAIFL ++ +++ 652 TLWYRAPEV+++ ++++ 659 ILFPDIIARA + +++ 662 KIQEILTQV + +++ 663 KIQEMQHFL + +++

TABLE 12B in vitro immunogenicity of additional HLA class I  peptides of the invention. Exemplary results of in vitro immunogenicity experiments conducted by the applicant for HLA-A*02 restricted peptides of the invention. Results of in vitro immunogenicity experiments are indicated.   Percentage of positive wells and donors(among evaluable) are summarized as indicated  <20% = +; 20%-49% = ++;  50%-69% = +++; >=70% = ++++ SEQ ID NO: Sequence Wells positive [%]   2SLLEADPFL “+”   3 SLASKLTTL “+”   5 HLTEVYPEL “+++”   7 SLVGLLLYL “++”  8 FTLGNVVGMYL “+”  11 KIFEMLEGV “+”  17 GLLPGDRLVSV “++”  19FMVDNEAIYDI “++”  36 YVLEDLEVTV “+”  38 FLLEDDIHVS “+”  40 TLLVKVFSV“++”  48 ALAELYEDEV “+”  49 YLPAVFEEV “++”  56 KLYEGIPVLL “+”  60SLTIDGIYYV “++++”  61 FLQGYQLHL “++”  79 SLFIGEKAVLL “+” 108 ALFPGVALLLA“++” 113 GLLPTPLFGV “+” 118 KLIDNNINV “+” 141 YLDFSNNRL “+” 143LLLDITPEI “+” 150 RLWEEGEELEL “+” 152 ILFEDIFDV “++” 157 SLNDEVPEV “+++”166 YLNHLEPPV “++++” 191 LLQEGQALEYV “+++” 198 KTINKVPTV “++” 199ALQDVPLSSV “+” 215 QLINHLHAV “++” 242 AIAYILQGV “+++” 247 VLLPNDLLEKV“+” 319 SLEPQIQPV “+” 384 ILFANPNIFV “+” 395 ALALGGIAVV “+++” 443GLWEIENNPTV “+” 446 QLIPALAKV “++” 454 KLPPPPPQA “++” 460 AMLEKNYKL “+”463 SLVESHLSDQLTL “++” 489 KMWEELPEVV “+” 499 KIFDIDEAEEGV “+” 511FLDPYCSASV “+” 518 KLNAEVACV “++” 603 FLIEPEHVNTV “+”

Example 4

Synthesis of Peptides

All peptides were synthesized using standard and well-established solidphase peptide synthesis using the Fmoc-strategy. Identity and purity ofeach individual peptide have been determined by mass spectrometry andanalytical RP-HPLC. The peptides were obtained as white to off-whitelyophilizates (trifluoro acetate salt) in purities of >50%. All TUMAPsare preferably administered as trifluoro-acetate salts or acetate salts,other salt-forms are also possible.

Example 5

MHC Binding Assays

Candidate peptides for T cell based therapies according to the presentinvention were further tested for their MHC binding capacity (affinity).The individual peptide-MHC complexes were produced by UV-ligandexchange, where a UV-sensitive peptide is cleaved upon UV-irradiation,and exchanged with the peptide of interest as analyzed. Only peptidecandidates that can effectively bind and stabilize the peptide-receptiveMHC molecules prevent dissociation of the MHC complexes. To determinethe yield of the exchange reaction, an ELISA was performed based on thedetection of the light chain (β2m) of stabilized MHC complexes. Theassay was performed as generally described in Rodenko et al. (Rodenko etal., 2006).

96 well MAXISorp plates (NUNC) were coated over night with 2 ug/mlstreptavidin in PBS at room temperature, washed 4× and blocked for 1 hat 37° C. in 2% BSA containing blocking buffer. RefoldedHLA-A*02:01/MLA-001 monomers served as standards, covering the range of15-500 ng/ml. Peptide-MHC monomers of the UV-exchange reaction werediluted 100 fold in blocking buffer. Samples were incubated for 1 h at3700, washed four times, incubated with 2 ug/ml HRP conjugated anti-β2mfor 1h at 3700, washed again and detected with TMB solution that isstopped with NH2SO4. Absorption was measured at 450 nm. Candidatepeptides that show a high exchange yield (preferably higher than 50%,most preferred higher than 75%) are generally preferred for a generationand production of antibodies or fragments thereof, and/or T cellreceptors or fragments thereof, as they show sufficient avidity to theMHC molecules and prevent dissociation of the MHC complexes.

TABLE 11  MHC class I binding scores. Binding of HLA-class I restricted peptides to HLA-A*02:01 was ranged by peptide exchange yield: ≥10% = +; ≥20% = ++; ≥50 = +++; ≥75% = ++++ SEQID SequencePeptide exchange 1 SLMEPPAVLLL “+++” 2 SLLEADPFL “+++” 3 SLASKLTTL“++++” 4 GIMEHITKI “++++” 5 HLTEVYPEL “+++” 6 VLVSDGVHSV “+++” 7SLVGLLLYL “++++” 8 FTLGNVVGMYL “++++” 9 GAAKDLPGV “++” 10 FLATFPLAAV“++++” 11 KIFEMLEGV “+++” 12 SLWPDPMEV “+++” 13 YLMDESLNL “+++” 14AAYGGLNEKSFV “+++” 15 VLLTFKIFL “++” 16 VLFQGQASL “+++” 17 GLLPGDRLVSV“+++” 18 YLVAKLVEV “++” 19 FMVDNEAIYDI “++++” 20 RMIEYFIDV “+++” 21VLDELDMEL “++” 22 IMEENPGIFAV “+++” 23 VLLDDIFAQL “+++” 24 SLSDGLEEV“++” 25 FLPDEPYIKV “+++” 26 ALLELAEEL “+++” 27 ILADIVISA “+++” 28QLLDETSAITL “+++” 29 KMLGIPISNILMV “+++” 30 LILDWVPYI “+++” 31YLAPELFVNV “++” 32 KLDDLTQDLTV “++” 33 VLLSLLEKV “++” 34 ILVEADSLWVV“+++” 35 KINDTIYEV “+++” 36 YVLEDLEVTV “++” 38 FLLEDDIHVS “+++” 39SVAPNLPAV “+++” 40 TLLVKVFSV “+++” 41 SLMPHIPGL “+++” 42 VLLQKIVSA “+++”43 VLSSLEINI “++” 44 ILDPISSGFLL “++” 45 SLWQDIPDV “+++” 46 ILTEENIHL“+++” 47 ILLSVPLLVV “++” 48 ALAELYEDEV “+++” 49 YLPAVFEEV “+++” 50SLSELEALM “+++” 51 LLPDLEFYV “++++” 52 FLLAHGLGFLL “++++” 53 KMIETDILQKV“++++” 54 SLLEQGKEPWMV “+++” 55 SLLDLETLSL “++++” 56 KLYEGIPVLL “++++”57 TLAELQPPVQL “+++” 58 FLDTLKDLI “+++” 59 IMEDIILTL “+++” 60 SLTIDGIYYV“++++” 61 FLQGYQLHL “++++” 62 VLLDVSAGQLLM “++++” 63 YLLPSGGSVTL “++” 64YAAPGGLIGV “++” 66 FLDENIGGVAV “+++” 67 TLLAEALVTV “+++” 68 SLMELPRGLFL“++++” 69 FQLDPSSGVLVTV “+++” 70 GLLDYPVGV “+++” 71 GILARIASV “+++” 72SLLELDGINL “++++” 73 NIFDLQIYV “+++” 74 ALLDPEVLSIFV “+++” 75 GLLEVMVNL“+++” 76 ILIDSIYKV “+++” 77 ILVEADGAWVV “++++” 78 SLFSSLEPQIQPV “+++” 79SLFIGEKAVLL “+++” 80 FLYDNLVESL “++” 81 FLFSQLQYL “++” 82 FLSSVTYNL“+++” 83 ILAPTVMMI “+++” 84 VTFGEKLLGV “++” 85 KMSELRVTL “+++” 86NLIGKIENV “+++” 87 ALPEAPAPLLPHIT “++” 88 FLLVGDLMAV “+++” 89 YILPTETIYV“++++” 90 TLLQIIETV “+++” 91 IMQDFPAEIFL “++++” 92 YLIPFTGIVGL “++” 93LLQAIKLYL “++” 94 YLIDIKTIAI “++” 95 SVIPQIQKV “+++” 96 YIFTDNPAAV “+++”97 SLINGSFLV “+++” 98 LIIDQADIYL “+++” 99 ALVSKGLATV “++” 100 YLLSTNAQL“++++” 101 ILVGGGALATV “+++” 102 YLFESEGLVL “+++” 103 TLAEEVVAL “+++”104 STMEQNFLL “++++” 106 LLYDAVHIVSV “+++” 107 FLQPVDDTQHL “+++” 108ALFPGVALLLA “++++” 109 IILSILEQA “++++” 110 FLSQVDFEL “+++” 111YVWGFYPAEV “+++” 113 GLLPTPLFGV “+++” 114 SLVGEPILQNV “++” 115AIAGAGILYGV “++” 116 YHIDEEVGF “+” 117 ILPDGEDFLAV “+++” 118 KLIDNNINV“+++” 119 FLYIGDIVSL “++++” 120 ALLGIPLTLV “+++” 121 GVVDPRAISVL “++”122 FLLAEDDIYL “+++” 123 NLWDLTDASVV “+++” 124 ALYETELADA “++” 125VQIHQVAQV “+++” 126 VLAYFLPEA “++++” 127 KIGDEPPKV “++” 128 YLFDDPLSAV“++” 129 GLLDGGVDILL “+++” 130 FLWNGEDSALL “+++” 131 FVPPVTVFPSL “++”132 LLVEQPPLAGV “+++” 133 KVLSNIHTV “++” 134 YLQELIFSV “+++” 135ALSEVDFQL “+++” 136 YLADPSNLFVV “+++” 137 TLVLTLPTV “++++” 138YQYPRAILSV “+++” 139 SVMEVNSGIYRV “+++” 140 YMDAPKAAL “++” 141 YLDFSNNRL“++” 142 FLFATPVFI “+++” 143 LLLDITPEI “++++” 144 YIMEPSIFNTL “+++” 145FLATSGTLAGI “++” 146 SLATAGDGLIEL “++” 147 SLLEAVSFL “+++” 148 ALNPEIVSV“++” 149 NLLELFVQL “+++” 150 RLWEEGEELEL “+++” 151 KILQQLVTL “+++” 152ILFEDIFDV “+++” 153 FLIANVLYL “+” 154 ALDDGTPAL “++” 155 RVANLHFPSV“+++” 157 SLNDEVPEV “++” 158 KLFDVDEDGYI “+++” 159 GLVGNPLPSV “++++” 160FLFDEEIEQI “+++” 161 ALLEGVNTV “+++” 162 YQQAQVPSV “+++” 163 ALDEMGDLLQL“+++” 164 ALLPQPKNLTV “+++” 165 SLLDEIRAV “+++” 166 YLNHLEPPV “++++” 167KVLEVTEEFGV “+++” 168 KILDADIQL “++++” 169 NLPEYLPFV “+++” 170 RLQETLSAA“+++” 171 LLLPLQILL “+++” 172 VLYSYTIITV “++” 173 LLDSASAGLYL “+++” 174ALAQYLITA “+++” 175 YLFENISQL “+++” 176 YLMEGSYNKVFL “++” 177YLLPEEYTSTL “++++” 178 ALTEIAFVV “++++” 179 KVLNELYTV “+++” 180FQIDPHSGLVTV “++” 181 LLWAGTAFQV “+++” 182 MLLEAPGIFL “+++” 183FGLDLVTEL “+++” 184 YLMDINGKMWL “+++” 185 FLIDDKGYTL “++” 186 TLFFQQNAL“++” 187 RQISIRGIVGV “+++” 188 GLFPVTPEAV “+++” 189 ALQRKLPYV “+++” 190FLSSLTETI “+++” 191 LLQEGQALEYV “++” 192 KMLDGASFTL “+++” 193QLLDADGFLNV “+++” 194 ALPLFVITV “+++” 195 GLFADLLPRL “+++” 196 YLYSVEIKL“++++” 197 ALGPEGGRV “++” 198 KTINKVPTV “+++” 199 ALQDVPLSSV “+++” 200LLFGSVQEV “+++” 201 RLVDYLEGI “+++” 202 ALLDQQGSRWTL “+++” 204 KIAENVEEV“++” 205 SLYPGTETMGL “+++” 206 VLQEGKLQKLAQL “+++” 207 GLTSTNAEV “++”208 KISPVTFSV “+++” 209 KLIESKHEV “++” 210 LLLNAVLTV “++” 211 LLWPGAALL“++” 212 ALWDQDNLSV “++” 214 FLLDLDPLLL “+++” 215 QLINHLHAV “+++” 216NLWEDPYYL “+++” 217 ALIHPVSTV “++” 218 SALEELVNV “++” 219 KLSDIGITV“+++” 220 LLQKFVPEI “++” 221 ALYEEGLLL “++” 222 NLIENVQRL “++” 223ALLENIALYL “+++” 224 TLIDAQWVL “+++” 225 SLLKVLPAL “+++” 226 MLYVVPIYL“++” 227 ALMNTLLYL “++” 228 AMQEYIAVV “++” 229 RLPGPLGTV “++” 230ILVDWLVEV “+” 231 FLSPQQPPLLL “++” 232 ALLEAQDVELYL “++” 233 VLSETLYEL“++” 234 ALMEDTGRQML “++” 235 YLNDLHEVLL “++++” 236 GLLEAKVSL “+++” 237ALLEASGTLLL “++++” 238 YLISFQTHI “+++” 239 AAFAGKLLSV “+++” 240ILLEQAFYL “+++” 241 SLVEVNPAYSV “+++” 242 AIAYILQGV “++” 243 LLLNELPSV“+++” 244 SLFGGTEITI “+++” 245 SMIDDLLGV “+++” 246 LLWEVVSQL “+++” 247VLLPNDLLEKV “+++” 248 FLFPNQYVDV “+++” 249 LLDGFLVNV “+++” 250ALSEEGLLVYL “++++” 251 ALYTGFSILV “++” 252 LLIGTDVSL “+++” 253 GLDAATATV“++” 254 TLLAFIMEL “+++” 255 VLASYNLTV “+++” 256 FLPPEHTIVYI “+++” 257SIFSAFLSV “+++” 258 ELAERVPAI “++” 261 YVLEFLEEI “++” 262 LLWGDLIWL“+++” 263 LLVSNLDFGV “+++” 264 SLQEQLHSV “+++” 265 LLFGGTKTV “++” 266KITDTLIHL “+++” 267 ALQDFLLSV “+++” 269 RVLEVGALQAV “++” 270 LLLDEEGTFSL“++” 271 LVYPLELYPA “+++” 272 ALGNTVPAV “+++” 273 NLFQSVREV “++” 274SLLFSLFEA “++” 275 YLVYILNEL “++” 276 ALFTFSPLTV “+++” 277 LLPPLESLATV“++” 278 QLLDVVLTI “++” 279 ALWGGTQPLL “++” 280 VLPDPEVLEAV “+++” 281ILRESTEEL “+++” 282 LLADVVPTT “+++” 283 ALYIGDGYVIHLA “+++” 284ILLSQTTGV “+++” 285 QLLHVGVTV “+++” 286 YLFPGIPEL “+++” 287 FLNEFFLNV“+++” 288 NLINEINGV “+++” 289 VLLEIEDLQV “++++” 295 VLDRESPNV “+++” 296FMEGAIIYV “+++” 297 VLADIELAQA “+++” 298 VMITKLVEV “+++” 299 YLLETSGNL“+++” 300 ALLGQTFSL “+++” 301 FLVEDLVDSL “+++” 302 ALLQEGEVYSA “+++” 303AILPQLFMV “++++” 304 MTLGQIYYL “+++” 305 SIANFSEFYV “++++” 306 ALVNVQIPL“+++” 307 ALPVSLPQI “+++” 308 SQYSGQLHEV “+++” 309 GLFDGVPTTA “+++” 310FLVDTPLARA “++++” 311 RLYTGMHTV “+++” 312 IISDLTIAL “+++” 313 VLFDDELLMV“+++” 314 ALIAEGIALV “+++” 315 YLQDVVEQA “+++” 316 ILLERLWYV “+++” 317SLAALVVHV “+++” 318 GLINTGVLSV “++” 319 SLEPQIQPV “++” 320 KMFEFVEPLL“++++” 321 GLFEDVTQPGILL “++++” 322 TLMTSLPAL “+++” 324 FLYDEIEAEV “+++”325 FIMPATVADATAV “+++” 326 FLPEALDFV “+++” 327 GLAPFTEGISFV “+++” 328ALNDQVFEI “+++” 329 FLVTLNNVEV “++++” 330 QLALKVEGV “+++” 331 KVDTVWVNV“+++” 332 YLISELEAA “+++” 333 FLPDANSSV “++” 334 TLTKVLVAL “+++” 335YSLSSVVTV “+++” 336 ILLTAIVQV “+++” 337 HLLSELEAAPYL “++++” 339GLWEIENNPTVKA “++++” 340 ALLSMTFPL “++++” 341 SQIALNEKLVNL “+++” 342HIYDKVMTV “+++” 343 SLLEVNEESTV “+++” 344 YLQDQHLLLTV “+++” 345VIWKALIHL “+++” 346 LLDSKVPSV “+++” 347 SLFKHDPAAWEA “++++” 348ILLDVKTRL “++++” 349 SLTEYLQNV “++++” 350 ALLDVTHSELTV “+++” 351SLIPNLRNV “+++” 352 SLLELLHIYV “+++” 353 YLFEMDSSL “++” 354 LILEGVDTV“++” 355 SIQQSIERLLV “++” 356 KLLGKLPEL “+++” 357 SMHDLVLQV “+++” 358ALDEYTSEL “++++” 359 YLLPESVDL “+++” 361 ALYELEGTTV “+++” 362 TLYGLSVLL“+++” 363 KVLDVSDLESV “++” 364 LLQNEQFEL “+++” 365 YVIDQGETDVYV “+++”366 RLLDMGETDLML “+++” 367 SLQNHNHQL “+++” 369 GLFPEHLIDV “+++” 370SLLQDLVSV “+++” 371 FLQAHLHTA “++++” 372 TMLLNIPLV “++” 373 SLLEDKGLAEV“++” 374 FLLQQHLISA “++” 375 SLTETIEGV “++” 376 AMFESSQNVLL “++” 377FLLDSSASV “++” 378 ALGYFVPYV “+++” 379 IMEGTLTRV “++” 380 TLIEDEIATI“++” 381 FIDEAYVEV “++” 382 ALQNYIKEA “++” 383 ALLELENSVTL “+++” 384ILFANPNIFV “+++” 385 SLLEQGLVEA “++” 386 ILFRYPLTI “+++” 387 ALFQATAEV“++++” 388 SLTIDGIRYV “+++” 389 LLADVTHLL “++” 390 ALFMKQIYL “+++” 391YVYPQRLNFV “+++” 392 ALLHPQGFEV “++” 393 GLLDTQTSQVLTA “++” 394LLAVIGGLVYL “+++” 395 ALALGGIAVV “++++” 396 ALLPDLPAL “+++” 397YLFGERLLEC “+++” 398 KLLEEDGTIITL “++” 399 YLFEPLYHV “+++” 400SLLTEQDLWTV “++” 401 ILLDDTGLAYI “+++” 402 VLFSGALLGL “++” 403 KLYDRILRV“++” 405 ALYDVFLEV “++” 407 YLMDLINFL “+++” 408 VLDDSIYLV “++” 409LLDAMNYHL “++” 412 YLDDLNEGVYI “++” 426 RLADKSVLV “+++” 427 ALLPLSPYL“+++” 428 KLGHTDILVGV “++” 429 GLVNDLARV “++” 430 HLYSSIEHLTT “+++” 431SLVNVVPKL “++” 432 TLIEESAKV “++” 433 AMLNEPWAV “+++” 434 KVSNSGITRV“++” 436 HLAEVSAEV “+++” 437 SMAPGLVIQAV “+++” 438 KLLPLAGLYL “++++” 439YLLQEIYGI “+++” 440 ALADGVTMQV “++” 441 ALLENPKMEL “+++” 442 GLLGGGGVLGV“+++” 443 GLWEIENNPTV “+++” 444 GLLRDEALAEV “+++” 446 QLIPALAKV “+++”447 QLVPALAKV “++” 448 NLLETKLQL “+++” 449 KLAEGLDIQL “+++” 450FMIDASVHPTL “+++” 451 LLLLDTVTMQV “++” 452 ILLEHGADPNL “+++” 453KLLEATSAV “++” 454 KLPPPPPQA “+++” 455 SLLKEPQKVQL “++” 456 LLIGHLERV“+++” 457 SLLPGNLVEKV “+++” 458 SLIDKLYNI “++” 459 ALITEVVRL “++” 460AMLEKNYKL “++++” 461 VMFRTPLASV “++” 462 KLAKQPETV “+++” 463SLVESHLSDQLTL “+++” 464 ALNDCIYSV “+++” 465 QLCDLNAEL “+++” 466VLIANLEKL “++++” 467 FLAKDFNFL “+++” 468 YLRSVGDGETV “+++” 469YLASDEITTV “+++” 471 YLYNNMIAKI “+++” 472 KLLEVSDDPQV “+++” 473AMATESILHFA “+++” 474 YLDPALELGPRNV “+++” 475 LLLNEEALAQI “+++” 476ALMERTGYSMV “+++” 477 ALLPASGQIAL “+++” 478 YLLHEKLNL “+++” 479SLFGNSGILENV “+++” 480 ALLEDSCHYL “+++” 481 GLIEDYEALL “+++” 484SLIEKVTQL “+++” 485 NVPDSFNEV “+++” 486 AVMESIQGV “+++” 487 LLINSVFHV“+++” 488 FLAEDPKVTL “+++” 489 KMWEELPEVV “+++” 490 FLLQHVQEL “+++” 491GLNDRSDAV “++” 492 SLFDGFADGLGV “+++” 493 GLLGEKTQDLIGV “+++” 494ALQPEPIKV “++” 495 FIFSEKPVFV “+++” 496 FLVEKQPPQV “+++” 497 GLLEKLTAI“+++” 498 KLWTGGLDNTV “+++” 499 KIFDIDEAEEGV “++” 500 SLMEDQVLQL “+++”501 LLDPNVKSIFV “+++” 502 RLLAQVPGL “+++” 503 SLNHFTHSV “+++” 504GLSDGNPSL “++” 505 SLAPGDVVRQV “++” 506 KLLGKVETA “+++” 507 KLIDDQDISISL“+++” 508 ILAQEQLVVGV “+++” 509 FLFDTKPLIV “+++” 510 KLYSVVSQL “++” 511FLDPYCSASV “++” 512 SLSEIVPCL “+++” 513 SLWPSPEQL “++” 514 ILVDWLVQV“+++” 515 LLQELVLFL “+++” 516 AVGPASILKEV “++” 517 LLMPIPEGLTL “+++” 518KLNAEVACV “+++” 519 GLLHLTLLL “+++” 520 LAVHPSGVAL “+” 521 MLLTKLPTI“+++” 522 TLWYRSPEV “++” 523 YQIPRTFTL “++” 524 ALIENLTHQI “++” 525VLLEAGEGLVTI “+++” 526 RLAEVGQYEQV “++” 527 FLLEPGNLEV “++++” 528SVAEGRALMSV “+++” 529 LLADELITV “+++” 530 VMYADIGGMDI “+++” 531YTLPIASSIRL “+++” 537 TLAPGEVLRSV “+++” 538 LLLAHIIAL “++” 539 ALFDAQAQV“+++” 541 SMLEPVPEL “+++” 542 RVWDISTVSSV “+++” 543 GLLPTPITQQASL “+++”544 LLWDVPAPSL “+++” 545 LLADLLHNV “+++” 546 VMIAGKVAVV “+++” 547TLDITPHTV “+++” 548 ALWENPESGEL “++” 549 AMLENASDIKL “+++” 550FLYDEIEAEVNL “+++” 551 KLYESLLPFA “+++” 552 GLLDLPFRVGV “++++” 553SLLNQDLHWSL “++++” 554 LLMPSSEDLLL “+++” 555 YVLEGLKSV “+++” 556FLTDLEDLTL “+++” 557 KLYDDMIRL “+++” 558 GLLENIPRV “+++” 559 VTVPPGPSL“++” 560 ALWDIETGQQTTT “+++” 561 YLQLTQSEL “+++” 562 YLEELPEKLKL “+++”563 WLLPYNGVTV “+++” 564 TVTNAVVTV “+++” 565 ALQETPTSV “++” 566VIADGGIQNV “++” 567 SLLPLDDIVRV “+++” 568 TLYDIAHTPGV “++++” 569KLVDRTWTL “+++” 570 ALANQIPTV “++” 571 LLLTTIPQI “+++” 572 ALADLIEKELSV“+++” 573 ILVANAIVGV “+++” 574 YLLQEPPRTV “++” 575 YLISQVEGHQV “+++” 576ILLNNSGQIKL “++++” 577 VMFEDGVLMRL “+++” 578 FLDPGGPMMKL “+++” 579NLMEMVAQL “++” 580 LLMENAERV “++” 582 TLCDVILMV “+++” 583 ILANDGVLLAA“+++” 584 ALAEVAAMENV “+++” 585 ALWDLAADKQTL “++++” 586 KLKPGDLVGV “+++”587 VMNDRLYAI “+++” 588 SLLPLSHLV “+++” 589 KLYPQLPAEI “+++” 590SLIEKLWQT “++” 591 SMAELDIKL “+++” 592 RLLJAAENFL “+++” 593 GLPRFGIEMV“+++” 594 IMLKGDNITL “+++” 595 VLLSIYPRV “+++” 596 ALLDQTKTLAESAL “+++”597 KLLEGQVIQL “+++” 598 FLFPHSVLV “+++” 599 YLLNDASLISV “+++” 600ALAAPDIVPAL “+++” 601 SAFPFPVTV “+++” 602 YLLEQIKLIEV “++++” 603FLIEPEHVNTV “++” 604 SILDRDDIFV “+++” 605 KLYEAVPQL “+++” 606 ALWETEVYI“+++” 607 RLYSGISGLEL “+++” 608 SLLSVSHAL “+++” 609 ALWKQLLEL “+++” 610LLAPTPYIIGV “+++” 611 YLLDDGTLVV “++++” 612 YLYNEGLSV “+++” 613RLLPPGAVVAV “+++” 614 LLLPDQPPYHL “+++” 615 VLPPDTDPA “++” 616 VLIDEVESL“+++” 617 ALMYESEKVGV “+++” 618 VLFDSESIGIYV “+++” 619 ALQDRVPLA “+++”620 KLLNKIYEA “+++” 621 VLMDRLPSLL “++++” 622 RLLGEEVVRVLQA “++++” 623YLVEDIQHI “+++” 635 SLDSTLHAV “+++”

Example 6

Absolute Quantitation of Tumor Associated Peptides Presented on the CellSurface

The generation of binders, such as antibodies and/or TCRs, is alaborious process, which may be conducted only for a number of selectedtargets. In the case of tumor-associated and -specific peptides,selection criteria include but are not restricted to exclusiveness ofpresentation and the density of peptide presented on the cell surface.In addition to the isolation and relative quantitation of peptides asdescribed in EXAMPLE 1, the inventors did analyze absolute peptidecopies per cell as described in patent application PCT/EP2015/79873. Thequantitation of TUMAP copies per cell in solid tumor samples requiresthe absolute quantitation of the isolated TUMAP, the efficiency of TUMAPisolation, and the cell count of the tissue sample analyzed.Experimental steps are described below.

Peptide Quantitation by nanoLC-MS/MS

For an accurate quantitation of peptides by mass spectrometry, acalibration curve was generated for each peptide using the internalstandard method. The internal standard is a double-isotope-labelledvariant of each peptide, i.e. two isotope-labelled amino acids wereincluded in TUMAP synthesis. It differs from the tumor-associatedpeptide only in its mass but shows no difference in otherphysicochemical properties (Anderson et al., 2012). The internalstandard was spiked to each MS sample and all MS signals were normalizedto the MS signal of the internal standard to level out potentialtechnical variances between MS experiments.

The calibration curves were prepared in at least three differentmatrices, i.e. HLA peptide eluates from natural samples similar to theroutine MS samples, and each preparation was measured in duplicate MSruns. For evaluation, MS signals were normalized to the signal of theinternal standard and a calibration curve was calculated by logisticregression.

For the quantitation of tumor-associated peptides from tissue samples,the respective samples were also spiked with the internal standard; theMS signals were normalized to the internal standard and quantified usingthe peptide calibration curve.

Efficiency of Peptide/MHC Isolation

As for any protein purification process, the isolation of proteins fromtissue samples is associated with a certain loss of the protein ofinterest. To determine the efficiency of TUMAP isolation, peptide/MHCcomplexes were generated for all TUMAPs selected for absolutequantitation. To be able to discriminate the spiked from the naturalpeptide/MHC complexes, single-isotope-labelled versions of the TUMAPswere used, i.e. one isotope-labelled amino acid was included in TUMAPsynthesis. These complexes were spiked into the freshly prepared tissuelysates, i.e. at the earliest possible point of the TUMAP isolationprocedure, and then captured like the natural peptide/MHC complexes inthe following affinity purification. Measuring the recovery of thesingle-labelled TUMAPs therefore allows conclusions regarding theefficiency of isolation of individual natural TUMAPs.

The efficiency of isolation was analyzed in a low number of samples andwas comparable among these tissue samples. In contrast, the isolationefficiency differs between individual peptides. This suggests that theisolation efficiency, although determined in only a limited number oftissue samples, may be extrapolated to any other tissue preparation.However, it is necessary to analyze each TUMAP individually as theisolation efficiency may not be extrapolated from one peptide to others.

Determination of the Cell Count in Solid, Frozen Tissue

In order to determine the cell count of the tissue samples subjected toabsolute peptide quantitation, the inventors applied DNA contentanalysis. This method is applicable to a wide range of samples ofdifferent origin and, most importantly, frozen samples (Alcoser et al.,2011; Forsey and Chaudhuri, 2009; Silva et al., 2013). During thepeptide isolation protocol, a tissue sample is processed to a homogenouslysate, from which a small lysate aliquot is taken. The aliquot isdivided in three parts, from which DNA is isolated (QiaAmp DNA Mini Kit,Qiagen, Hilden, Germany). The total DNA content from each DNA isolationis quantified using a fluorescence-based DNA quantitation assay (QubitdsDNA HS Assay Kit, Life Technologies, Darmstadt, Germany) in at leasttwo replicates.

In order to calculate the cell number, a DNA standard curve fromaliquots of single healthy blood cells, with a range of defined cellnumbers, has been generated. The standard curve is used to calculate thetotal cell content from the total DNA content from each DNA isolation.The mean total cell count of the tissue sample used for peptideisolation is extrapolated considering the known volume of the lysatealiquots and the total lysate volume.

Peptide Copies Per Cell

With data of the aforementioned experiments, the inventors calculatedthe number of TUMAP copies per cell by dividing the total peptide amountby the total cell count of the sample, followed by division throughisolation efficiency. Copy cell number for selected peptides are shownin Table 12

TABLE 12Absolute copy numbers. The table lists the results of absolute peptidequantitation in NSCLC tumor samples. The median number of copies per cell are indicated for each peptide: <100 = +; >=100 = ++; >=1,000 +++; >=10,000 = ++++. Thenumber of samples, in which evaluable, high quality MS data are available, is indicated. Seq ID Sequence Copy Number CategoryNumber of quantifiable samples  11 KIFEMLEGV ++ 32 198 KTINKVPTV ++ 14408 VLDDSIYLV ++ 17 427 ALLPLSPYL +++ 13 587 VMNDRLYAI ++ 18

REFERENCE LIST

-   Nature 511 (2014): 543-550-   Abba, M. C. et al., Mol. Cancer Res 5 (2007): 881-890-   Abdelmalak, C. A. et al., Clin Lab 60 (2014): 55-61-   Abele, R. et al., Essays Biochem. 50 (2011): 249-264-   Abetamann, V. et al., Clin Cancer Res 2 (1996): 1607-1618-   Abuhusain, H. J. et al., J Biol Chem 288 (2013): 37355-37364-   Adam, A. P. et al., Cancer Res 69 (2009): 5664-5672-   Addou-Klouche, L. et al., Mol. Cancer 9 (2010): 213-   Adelaide, J. et al., Cancer Res 67 (2007): 11565-11575-   Adelman, C. A. et al., Nature 502 (2013): 381-384-   Adhikary, S. et al., Cell 123 (2005): 409-421-   Agarwal, A. K. et al., J Lipid Res 51 (2010): 2143-2152-   Agarwal, N. et al., Oncogene 32 (2013): 462-470-   Agesen, T. H. et al., Gut 61 (2012): 1560-1567-   Ahangari, F. et al., Med. Oncol 31 (2014): 173-   Ahsan, S. et al., Acta Neuropathol. Commun. 2 (2014): 59-   Aissani, B. et al., Genes Immun. 15 (2014): 424-429-   Aissani, B. et al., Fertil. Steril. 103 (2015): 528-534-   Ajiro, M. et al., Int. J Oncol 35 (2009): 673-681-   Ajiro, M. et al., Int. J Oncol 37 (2010): 1085-1093-   Akao, Y. et al., Cancer Res 55 (1995): 3444-3449-   Akino, K. et al., Cancer Sci. 98 (2007): 88-95-   Akisawa, Y. et al., Virchows Arch. 442 (2003): 66-70-   Al-haidari, A. A. et al., Int. J Colorectal Dis. 28 (2013):    1479-1487-   Albulescu, R., Biomark. Med. 7 (2013): 203-   Alimirah, F. et al., Mol. Cancer Res 5 (2007): 251-259-   Allen, T. et al., Cancer Res 66 (2006): 1294-1301-   Allera-Moreau, C. et al., Oncogenesis. 1 (2012): e30-   Allison, J. P. et al., Science 270 (1995): 932-933-   Alpizar-Alpizar, W. et al., Int. J Cancer 131 (2012): E329-E336-   Alvarez, J. V. et al., Cancer Cell 24 (2013): 30-44-   Aly, R. M. et al., Blood Cells Mol. Dis. 53 (2014): 185-188-   Amini, S. et al., Anat. Cell Biol 47 (2014): 1-11-   Amos, C. I. et al., Hum. Mol. Genet. 20 (2011): 5012-5023-   An, C. H. et al., Pathol. Oncol Res 21 (2015): 181-185-   Anchi, T. et al., Oncol Lett. 3 (2012): 264-268-   Andersen, C. L. et al., Br. J Cancer 100 (2009): 511-523-   Andersen, J. B. et al., Br. J Cancer 94 (2006): 1465-1471-   Andersen, J. N. et al., Sci. Transl. Med. 2 (2010): 43ra55-   Andersen, R. S. et al., Nat. Protoc. 7 (2012): 891-902-   Anderson, K. S. et al., J Proteome. Res 10 (2011): 85-96-   Andrade, V. C. et al., Exp. Hematol. 37 (2009): 446-449-   Andrew, A. S. et al., Hum. Genet. 125 (2009): 527-539-   Angele, S. et al., Br. J Cancer 91 (2004): 783-787-   Ansari, D. et al., J Cancer Res Clin Oncol 141 (2015): 369-380-   Antony-Debre, I. et al., Cancer Cell 27 (2015): 609-611-   Appay, V. et al., Eur. J Immunol. 36 (2006): 1805-1814-   Arai, A. et al., Cancer Res 71 (2011): 4598-4607-   Arai, E. et al., Int. J Cancer 135 (2014): 1330-1342-   Arbabian, A. et al., FEBS J 280 (2013): 5408-5418-   Arbitrio, M. et al., Cancer Chemother. Pharmacol. 77 (2016): 205-209-   Argani, P. et al., Clin Cancer Res 7 (2001): 3862-3868-   Arlt, A. et al., Oncogene 28 (2009): 3983-3996-   Arsenic, R. et al., BMC. Cancer 15 (2015): 784-   Asahara, S. et al., J Transl. Med. 11 (2013): 291-   Asmarinah, A. et al., Int. J Oncol 45 (2014): 1489-1496-   Asou, N. et al., Blood 109 (2007): 4023-4027-   Aviles, Velastegui J. et al., Minerva Chir 46 (1991): 533-537-   Ayala, F. et al., Breast Cancer Res Treat. 80 (2003): 145-154-   Aylon, Y. et al., Mol. Oncol 5 (2011): 315-323-   Azimi, A. et al., Br. J Cancer 110 (2014): 2489-2495-   Azzimonti, B. et al., Histopathology 45 (2004): 560-572-   Babron, M. C. et al., Carcinogenesis 35 (2014): 1523-1527-   Bachmann, S. B. et al., Mol Cancer 13 (2014): 125-   Bacsi, K. et al., BMC. Cancer 8 (2008): 317-   Bagheri, F. et al., Mol. Biol Rep. 41 (2014): 7387-7394-   Balakrishnan, A. et al., Hum. Mutat. 30 (2009): 1167-1174-   Baldini, E. et al., Andrologia 42 (2010): 260-267-   Balgkouranidou, I. et al., Clin Chem Lab Med. 51 (2013): 1505-1510-   Ball, A. R., Jr. et al., Mol. Cell Biol 22 (2002): 5769-5781-   Banat, G. A. et al., PLoS. One. 10 (2015): e0139073-   Banchereau, J. et al., Cell 106 (2001): 271-274-   Band, A. M. et al., J Mammary. Gland. Biol Neoplasia. 16 (2011):    109-115-   Bandoh, N. et al., Oncol Rep. 23 (2010): 933-939-   Bandres, E. et al., Oncol Rep. 12 (2004): 287-292-   Banerjee, R. et al., Nat Commun. 5 (2014): 4527-   Bao, B. Y. et al., Clin Cancer Res. 17 (2011): 928-936-   Bar-Peled, L. et al., Science 340 (2013): 1100-1106-   Barbarulo, A. et al., Oncogene 32 (2013): 4231-4242-   Bargou, R. C. et al., Nat Med. 3 (1997): 447-450-   Bartlett, J. M. et al., Br. J Cancer 113 (2015): 722-728-   Bauer, M. et al., Oncol Rep. 11 (2004): 677-680-   Bazzaro, M. et al., Am. J Pathol. 171 (2007): 1640-1649-   Beales, P. L. et al., Nephrol. Dial. Transplant. 15 (2000):    1977-1985-   Beard, R. E. et al., Clin Cancer Res 19 (2013): 4941-4950-   Beatty, G. et al., J Immunol 166 (2001): 2276-2282-   Bednarska, K. et al., Immunobiology 221 (2016): 323-332-   Beggs, J. D., Nature 275 (1978): 104-109-   Behrens, P. et al., Anticancer Res 21 (2001): 2413-2417-   Behrens, P. et al., Apoptosis. 8 (2003): 39-44-   Bekker-Jensen, S. et al., Nat Cell Biol 12 (2010): 80-86-   Benada, J. et al., Biomolecules. 5 (2015): 1912-1937-   Bender, C. et al., Int. J Cancer 131 (2012): E45-E55-   Benjamini, Y. et al., Journal of the Royal Statistical Society.    Series B (Methodological), Vol. 57 (1995): 289-300-   Bennett, C. B. et al., PLoS. One. 3 (2008): e1448-   Berger, C. et al., Curr. Mol. Med. 13 (2013): 1229-1240-   Bertherat, J. et al., Cancer Res 63 (2003): 5308-5319-   Bessho, Y. et al., Oncol Rep. 21 (2009): 263-268-   Bhan, S. et al., Oncol Rep. 28 (2012): 1498-1502-   Bhattacharya, C. et al., Mol Cancer 11 (2012): 82-   Bi, Q. et al., Clin Exp. Metastasis 32 (2015): 301-311-   Bi, W. et al., Oncol Rep. 29 (2013): 1533-1539-   Bianchi, E. et al., Cancer Res 54 (1994): 861-866-   Bidkhori, G. et al., PLoS. One. 8 (2013): e67552-   Bieche, I. et al., Int. J Cancer 133 (2013): 2791-2800-   Bieniek, J. et al., Prostate 74 (2014): 999-1011-   Bierkens, M. et al., Genes Chromosomes. Cancer 52 (2013): 56-68-   Bilbao-Aldaiturriaga, N. et al., Pediatr. Blood Cancer 62 (2015):    766-769-   Bin Amer, S. M. et al., Saudi. Med. J 29 (2008): 507-513-   Bisgrove, D. A. et al., J Biol Chem 275 (2000): 30668-30676-   Bish, R. et al., Mol. Cells 37 (2014): 357-364-   Bisikirska, B. C. et al., Oncogene 32 (2013): 5283-5291-   Blanco, I. et al., PLoS. One. 10 (2015): e0120020-   Blenk, S. et al., Cancer Inform. 3 (2007): 399-420-   Blenk, S. et al., BMC. Cancer 8 (2008): 106-   Bloch, D. B. et al., J Biol Chem 271 (1996): 29198-29204-   Bock, A. J. et al., Hum. Pathol. 43 (2012): 669-674-   Bode, P. K. et al., Mod. Pathol. 27 (2014): 899-905-   Boehrer, S. et al., Hematol. J 2 (2001): 103-107-   Boehringer, J. et al., Biochem. J 448 (2012): 55-65-   Bogush, T. A. et al., Antibiot. Khimioter. 54 (2009): 41-49-   Boland, A. et al., Nat Struct. Mol. Biol 20 (2013): 1289-1297-   Bombardieri, R. et al., Endocr. Pract. 19 (2013): e124-e128-   Borel, F. et al., Hepatology 55 (2012): 821-832-   Bossi, D. et al., Mol. Oncol 8 (2014): 221-231-   Boulter, J. M. et al., Protein Eng 16 (2003): 707-711-   Bourdon, V. et al., Cancer Res 62 (2002): 6218-6223-   Bourguignon, L. Y. et al., J Biol Chem 287 (2012): 32800-32824-   Brandacher, G. et al., Clin Cancer Res 12 (2006): 1144-1151-   Brandenberger, R. et al., Nat Biotechnol. 22 (2004): 707-716-   Braulke, T. et al., Arch. Biochem. Biophys. 298 (1992): 176-181-   Braumuller, H. et al., Nature (2013)-   Brendle, A. et al., Carcinogenesis 29 (2008): 1394-1399-   Brocke, K. S. et al., Cancer Biol Ther. 9 (2010): 455-468-   Broderick, P. et al., BMC. Cancer 6 (2006): 243-   Brody, J. R. et al., Cell Cycle 8 (2009): 1930-1934-   Brossart, P. et al., Blood 90 (1997): 1594-1599-   Brouland, J. P. et al., Am. J Pathol. 167 (2005): 233-242-   Brown, C. O. et al., Leuk. Res 37 (2013): 963-969-   Bruckdorfer, T. et al., Curr. Pharm. Biotechnol. 5 (2004): 29-43-   Brule, H. et al., Biochemistry 43 (2004): 9243-9255-   Brynczka, C. et al., BMC. Genomics 8 (2007): 139-   Bubnov, V. et al., Exp. Oncol 34 (2012): 370-372-   Buch, S. C. et al., Mol Carcinog. 51 Suppl 1 (2012): E11-E20-   Budowle, B. et al., Cancer Genet. Cytogenet. 5 (1982): 247-251-   Bueno, R. C. et al., Ann. Oncol 25 (2014): 69-75-   Bugide, S. et al., Oncogene 34 (2015): 4601-4612-   Bujo, H., Rinsho Byori 60 (2012): 469-476-   Bull, J. H. et al., Br. J Cancer 84 (2001): 1512-1519-   Burger, H. et al., Leukemia 8 (1994): 990-997-   Burkhart, R. A. et al., Mol. Cancer Res 11 (2013): 901-911-   Burleigh, A. et al., Breast Cancer Res 17 (2015): 4-   Burton, J. D. et al., Clin Cancer Res 10 (2004): 6606-6611-   Butz, H. et al., Clin Chem 60 (2014): 1314-1326-   Caballero, O. L. et al., PLoS. One. 5 (2010)-   Caceres-Gorriti, K. Y. et al., PLoS. One. 9 (2014): e91000-   Cahan, P. et al., BMC. Genomics 11 (2010): 638-   Cai, H. et al., PLoS. One. 8 (2013a): e57081-   Cai, H. et al., Cell Commun. Signal. 11 (2013): 31-   Cai, K. et al., Lin. Chung Er. Bi Yan. Hou Tou. Jing. Wai Ke. Za    Zhi. 26 (2012): 425-428-   Cai, W. et al., Cancer 119 (2013b): 1486-1494-   Caldarelli, A. et al., Leukemia 27 (2013): 2301-2310-   Calin, G. A. et al., Oncogene 19 (2000): 1191-1195-   Callahan, M. J. et al., Clin Cancer Res 14 (2008): 7667-7673-   Camgoz, A. et al., Leuk. Lymphoma 54 (2013): 1279-1287-   Campone, M. et al., Breast Cancer Res Treat. 109 (2008): 491-501-   Cantara, S. et al., J Clin Endocrinol. Metab 97 (2012): 4253-4259-   Cao, J. X. et al., Cell Death. Dis. 5 (2014): e1426-   Cao, L. et al., Biochem. Biophys. Res Commun. 333 (2005): 1050-1059-   Cappellari, M. et al., Oncogene 33 (2014): 3794-3802-   Card, K. F. et al., Cancer Immunol Immunother. 53 (2004): 345-357-   Caren, H. et al., BMC. Cancer 11 (2011): 66-   Carrascosa, C. et al., Oncogene 31 (2012): 1521-1532-   Carton, J. M. et al., J Histochem. Cytochem. 51 (2003): 715-726-   Cascon, A. et al., J Natl. Cancer Inst. 107 (2015)-   Castano-Rodriguez, N. et al., Front Immunol. 5 (2014): 336-   Castle, J. C. et al., BMC. Genomics 15 (2014): 190-   Castro, M. et al., J Transl. Med. 8 (2010): 86-   Ceol, C. J. et al., Nature 471 (2011): 513-517-   Cerhan, J. R. et al., Blood 110 (2007): 4455-4463-   Cerna, D. et al., J Biol Chem 287 (2012): 22408-22417-   Cerveira, N. et al., BMC. Cancer 10 (2010): 518-   Chae, S. W. et al., Yonsei Med. J 52 (2011): 445-453-   Chaigne-Delalande, B. et al., Science 341 (2013): 186-191-   Chan, A. O. et al., Gut 48 (2001): 808-811-   Chan, S. H. et al., Int. J Cancer 129 (2011): 565-573-   Chandramouli, A. et al., Carcinogenesis 28 (2007): 2028-2035-   Chang, C. C. et al., World J Gastroenterol. 20 (2014a): 6826-6831-   Chang, C. M. et al., Carcinogenesis 34 (2013): 2512-2520-   Chang, G. T. et al., Endocr. Relat Cancer 11 (2004): 815-822-   Chang, H. et al., Breast Cancer Res Treat. 125 (2011): 55-63-   Chang, K. et al., Proc. Natl. Acad. Sci. U.S.A 93 (1996): 136-140-   Chang, L. C. et al., Anticancer Drugs 25 (2014b): 456-461-   Chang, Y. C. et al., J Biol Chem 287 (2012): 4376-4385-   Chang, Y. T. et al., World J Gastroenterol. 20 (2014c): 14463-14471-   Chanock, S. J. et al., Hum. Immunol. 65 (2004): 1211-1223-   Chatterjee, M. et al., Haematologica 98 (2013): 1132-1141-   Chatterjee, M. et al., Blood 111 (2008): 3714-3722-   Chelli, B. et al., Chembiochem. 6 (2005): 1082-1088-   Chen, C. H. et al., Mol. Cancer 14 (2015a): 83-   Chen, C. H. et al., Oncogene 28 (2009a): 2723-2737-   Chen, C. H. et al., Oncotarget. 5 (2014a): 6300-6311-   Chen, C. H. et al., J Transl. Med. 10 (2012a): 93-   Chen, C. H. et al., Gynecol. Oncol 128 (2013a): 560-567-   Chen, H. et al., J Surg. Res 189 (2014b): 81-88-   Chen, H. J. et al., World J Gastroenterol. 19 (2013b): 3130-3133-   Chen, H. S. et al., Zhonghua Gan Zang. Bing. Za Zhi. 11 (2003):    145-148-   Chen, J. et al., Int. J Cancer 122 (2008): 2249-2254-   Chen, J. et al., Oncotarget. 6 (2015b): 355-367-   Chen, J. Q. et al., Horm. Cancer 1 (2010): 21-33-   Chen, K. et al., Nat Commun. 5 (2014c): 4682-   Chen, K. G. et al., Pigment Cell Melanoma Res 22 (2009b): 740-749-   Chen, L. et al., Oncol Rep. 34 (2015c): 447-454-   Chen, L. et al., Cell Mol. Biol (Noisy.-le-grand) 60 (2014d): 1-5-   Chen, L. et al., Cancer Res 65 (2005): 5599-5606-   Chen, L. C. et al., Mod. Pathol. 24 (2011): 175-184-   Chen, Q. et al., PLoS. One. 9 (2014e): e88386-   Chen, R. et al., Cancer Res 61 (2001): 654-658-   Chen, W. T. et al., Elife. 4 (2015d)-   Chen, X. et al., Pathol. Res Pract. 208 (2012b): 437-443-   Chen, X. et al., Med. Oncol 31 (2014f): 865-   Chen, X. P. et al., Asian Pac. J Cancer Prev. 15 (2014g): 7741-7746-   Chen, Y. et al., J Cell Biochem. 100 (2007): 1337-1345-   Chen, Y. et al., Am. J Physiol Lung Cell Mol. Physiol 306 (2014h):    L797-L807-   Chen, Y. et al., Int. J Cancer 91 (2001): 41-45-   Chen, Y. et al., J Hematol. Oncol 2 (2009c): 37-   Chen, Y. et al., Oncogene 32 (2013c): 4941-4949-   Chen, Y. et al., Onco. Targets. Ther. 7 (2014i): 1465-1472-   Chen, Y. T. et al., Int. J Cancer 124 (2009d): 2893-2898-   Chen, Y. T. et al., Proc. Natl. Acad. Sci. U.S.A 102 (2005):    7940-7945-   Chen, Z. T. et al., Int. J Mol. Sci. 16 (2015e): 15497-15530-   Cheng, A. N. et al., Cancer Lett. 337 (2013a): 218-225-   Cheng, A. S. et al., Gastroenterology 144 (2013b): 122-133-   Cheng, L. et al., Gynecol. Oncol 117 (2010): 159-169-   Cheng, S. et al., Int. J Clin Exp. Pathol. 7 (2014): 8118-8126-   Cheng, Y. et al., Cancer Genet. 204 (2011): 375-381-   Cheng, Y. et al., Clin Transl. Sci. 8 (2015a): 320-325-   Cheng, Z. et al., J Exp. Clin Cancer Res 34 (2015b): 27-   Chernikova, S. B. et al., Cancer Res 72 (2012): 2111-2119-   Chevillard, G. et al., Blood 117 (2011): 2005-2008-   Chi, L. M. et al., Mol. Cell Proteomics. 8 (2009): 1453-1474-   Chin, S. F. et al., Genome Biol 8 (2007): R215-   Chittasupho, C. et al., Mol. Pharm. 7 (2010): 146-155-   Cho, H. J. et al., DNA Cell Biol 35 (2016): 71-80-   Cho, S. et al., Proc. Natl. Acad. Sci. U.S.A 108 (2011): 20778-20783-   Choi, Y. L. et al., J Thorac. Oncol 9 (2014): 563-566-   Choi, Y. W. et al., Int. J Gynecol. Cancer 17 (2007): 687-696-   Choschzick, M. et al., Hum. Pathol. 41 (2010): 358-365-   Chou, J. L. et al., Clin Epigenetics. 7 (2015): 1-   Chowdhury, S. K. et al., Biochem. Biophys. Res Commun. 333 (2005):    1139-1145-   Chowdhury, S. K. et al., Free Radic. Res 41 (2007): 1116-1124-   Chu, X. et al., Biochem. Biophys. Res Commun. 447 (2014): 158-164-   Chuang, J. Y. et al., Oncogene 31 (2012): 4946-4959-   Chung, F. Y. et al., J Surg. Oncol 102 (2010): 148-153-   Chung, K. Y. et al., Hepatology 54 (2011): 307-318-   Cicek, M. S. et al., Hum. Mol. Genet. 22 (2013): 3038-3047-   Cieply, B. et al., Cancer Res 72 (2012): 2440-2453-   Ciruelos Gil, E. M., Cancer Treat. Rev 40 (2014): 862-871-   Clarke, L. E. et al., J Cutan. Pathol. 36 (2009): 433-438-   Claudio, J. O. et al., Oncogene 20 (2001): 5373-5377-   Coe, H. et al., Int. J Biochem. Cell Biol 42 (2010): 796-799-   Cohen, C. J. et al., J Mol Recognit. 16 (2003a): 324-332-   Cohen, C. J. et al., J Immunol 170 (2003b): 4349-4361-   Cohen, S. N. et al., Proc. Natl. Acad. Sci. U.S.A 69 (1972):    2110-2114-   Cohen, Y. et al., Hematology. 19 (2014): 286-292-   Colak, D. et al., PLoS. One. 8 (2013): e63204-   Colas, E. et al., Int. J Cancer 129 (2011): 2435-2444-   Colbert, L. E. et al., Cancer Res 74 (2014): 2677-2687-   Cole, S. P. et al., Science 258 (1992): 1650-1654-   Coligan, J. E. et al., Current Protocols in Protein Science (1995)-   Colis, L. et al., J Med. Chem 57 (2014): 4950-4961-   Colombetti, S. et al., J Immunol. 176 (2006): 2730-2738-   Colombo, J. et al., Oncol Rep. 21 (2009): 649-663-   Condomines, M. et al., J Immunol. 178 (2007): 3307-3315-   Confalonieri, S. et al., Oncogene 28 (2009): 2959-2968-   Cong, X. et al., Hum. Pathol. 45 (2014): 1370-1378-   Cook, J. et al., Oncogene 18 (1999): 1205-1208-   Coppola, D. et al., J Geriatr. Oncol 5 (2014): 389-399-   Coradeghini, R. et al., Oncol Rep. 15 (2006): 609-613-   Corcoran, C. A. et al., Mol. Cancer Res 6 (2008): 795-807-   Cornelissen, M. et al., BMC. Cancer 3 (2003): 7-   Couch, F. J. et al., Cancer Res 65 (2005): 383-386-   Coupienne, I. et al., Lasers Surg. Med. 43 (2011): 557-564-   Creancier, L. et al., Cancer Lett. 365 (2015): 107-111-   Cubillos-Rojas, M. et al., J Biol Chem 289 (2014): 14782-14795-   Cuevas, I. C. et al., Cancer Res 65 (2005): 5070-5075-   Cuevas, R. et al., Cancer Res 73 (2013): 1400-1410-   Cui, D. X. et al., World J Gastroenterol. 11 (2005): 1273-1282-   Cui, F. et al., Proteomics. 6 (2006): 498-504-   Cui, L. H. et al., Med. Oncol 29 (2012): 1837-1842-   Cui, X. et al., Oncogene 26 (2007): 4253-4260-   Cunliffe, H. E. et al., Am. J Cancer Res 2 (2012): 478-491-   Cunningham, J. D. et al., Am. J Surg. 173 (1997): 521-522-   Cunningham, J. M. et al., Br. J Cancer 101 (2009): 1461-1468-   Curry, J. M. et al., Laryngoscope (2015)-   Cvekl, A., Jr. et al., Eur. J Cancer 40 (2004): 2525-2532-   Dadkhah, E. et al., Arch. Iran Med. 16 (2013): 463-470-   Dahlman, K. B. et al., PLoS. One. 7 (2012): e34414-   Dajon, M. et al., Oncoimmunology 4 (2015): e991615-   Dalamaga, M., Med. Hypotheses 79 (2012): 617-621-   Daly, R. J. et al., Oncogene 21 (2002): 5175-5181-   Dannenmann, S. R. et al., Cancer Immunol. Res. 1 (2013): 288-295-   Danussi, C. et al., Cancer Res 73 (2013): 5140-5150-   Das, A. et al., J Cell Sci. 127 (2014): 686-699-   Das, M. et al., PLoS. One. 8 (2013a): e69607-   Das, T. K. et al., Oncogene 32 (2013b): 3184-3197-   Dasari, V. K. et al., J Urol. 165 (2001): 1335-1341-   Dasgupta, S. et al., Int. J Oncol 41 (2012): 1405-1410-   Datta, M. W. et al., Appl. Immunohistochem. Mol. Morphol. 8 (2000):    210-215-   Davalieva, K. et al., Prostate 75 (2015): 1586-1600-   David-Watine, B., PLoS. One. 6 (2011): e22423-   Davidson, B. et al., J Cell Mol. Med. 15 (2011): 535-544-   Davydova, E. et al., J Biol Chem 289 (2014): 30499-30510-   De Angelis, P. M. et al., Mol. Cancer 5 (2006): 20-   de Leon, F. C. et al., Childs Nerv. Syst. 31 (2015): 141-146-   De, Paoli L. et al., Leuk. Lymphoma 54 (2013): 1087-1090-   De, S. et al., Cancer Res 69 (2009): 8035-8042-   Debauve, G. et al., Cell Mol Life Sci. 65 (2008): 591-604-   Deighton, R. F. et al., Brain Pathol. 20 (2010): 691-703-   DelBove, J. et al., Epigenetics. 6 (2011): 1444-1453-   Demelash, A. et al., Mol. Biol Cell 23 (2012): 2856-2866-   Demokan, S. et al., Int. J Cancer 127 (2010): 2351-2359-   Deng, S. et al., Breast Cancer Res Treat. 104 (2007): 21-30-   Deng, Y. C. et al., Ai. Zheng. 24 (2005): 680-684-   Dengjel, J. et al., Clin Cancer Res 12 (2006): 4163-4170-   Denkberg, G. et al., J Immunol 171 (2003): 2197-2207-   Desai, S. D. et al., Exp. Biol Med. (Maywood.) 237 (2012): 38-49-   Diao, C. Y. et al., Asian Pac. J Cancer Prev. 15 (2014): 1817-1822-   Diefenbacher, M. E. et al., J Clin Invest 124 (2014): 3407-3418-   Diggle, C. P. et al., PLoS. Genet. 10 (2014): e1004577-   DiSepio, D. et al., Proc. Natl. Acad. Sci. U.S.A 95 (1998):    14811-14815-   Dobashi, Y. et al., Int. J Cancer 110 (2004): 532-541-   Dohn, L. H. et al., Urol. Oncol 33 (2015): 165-24-   Doldan, A. et al., Mol. Carcinog 47 (2008a): 235-244-   Doldan, A. et al., Mol. Carcinog 47 (2008b): 806-813-   Domanitskaya, N. et al., Br. J Cancer 111 (2014): 696-707-   Dominguez-Sanchez, M. S. et al., BMC. Cancer 11 (2011): 77-   Donati, G. et al., J Cell Sci. 124 (2011): 3017-3028-   Dong, P. et al., Cancer Lett. 243 (2006): 120-127-   Dong, Q. et al., Biomed. Res Int. 2015 (2015): 156432-   Dong, W. et al., Tumour. Biol (2015)-   Donnellan, R. et al., FASEB J 13 (1999): 773-780-   Dorman, S. N. et al., Mol. Oncol (2015)-   Dormeyer, W. et al., J Proteome. Res 7 (2008): 2936-2951-   Douet-Guilbert, N. et al., Leuk. Res 38 (2014): 1316-1319-   Downie, D. et al., Clin Cancer Res. 11 (2005): 7369-7375-   Drazkowska, K. et al., Nucleic Acids Res 41 (2013): 3845-3858-   Du, C. et al., Gastric. Cancer 18 (2015a): 516-525-   Du, L. et al., Tumori 101 (2015b): 384-389-   Du, Y. et al., Int. J Mol. Sci. 15 (2014a): 17065-17076-   Du, Y. F. et al., Int. J Clin Exp. Pathol. 7 (2014b): 923-931-   Duan, X. L. et al., Zhongguo Shi Yan. Xue. Ye. Xue. Za Zhi. 21    (2013): 7-11-   Duarte-Pereira, S. et al., Sci. Rep. 4 (2014): 6311-   Duex, J. E. et al., Exp. Cell Res 316 (2010): 2136-2151-   Dun, B. et al., Am. J Transl. Res 6 (2013a): 28-42-   Dun, B. et al., Int. J Clin Exp. Pathol. 6 (2013b): 2880-2886-   Dunn, G. P. et al., Proc. Natl. Acad. Sci. U.S.A 111 (2014):    1102-1107-   Dunphy, E. J. et al., J Immunother. 28 (2005): 268-275-   Dunzendorfer, U. et al., Eur. Urol. 6 (1980): 232-236-   Durgan, J. et al., J Biol Chem 286 (2011): 12461-12474-   Dusseau, C. et al., Int. J Oncol 18 (2001): 393-399-   Duursma, A. et al., Mol. Cell Biol 25 (2005): 6937-6947-   Duvic, M. et al., Clin Cancer Res 6 (2000): 3249-3259-   Duvic, M. et al., J Invest Dermatol. 121 (2003): 902-909-   Dyrskjot, L. et al., Br. J Cancer 107 (2012): 116-122-   Dzikiewicz-Krawczyk, A. et al., J Hematol. Oncol 7 (2014): 43-   Eggers, J. P. et al., Clin Cancer Res 17 (2011): 6140-6150-   Eldai, H. et al., PLoS. One. 8 (2013): e76251-   Elgohary, N. et al., Int. J Oncol 46 (2015): 597-606-   Elias, D. et al., Oncogene 34 (2015): 1919-1927-   Ellison-Zelski, S. J. et al., Mol. Cancer 9 (2010): 263-   Emdad, L. et al., Neuro. Oncol 17 (2015): 419-429-   Emmanuel, C. et al., PLoS. One. 6 (2011): e17617-   Endoh, H. et al., J Clin Oncol 22 (2004): 811-819-   Enesa, K. et al., Adv. Exp. Med. Biol. 809 (2014): 33-48-   Eng, K. H. et al., Genes Cancer 6 (2015): 399-407-   Enomoto, A. et al., Eur. J Cancer 49 (2013): 3547-3558-   Epping, M. T. et al., Mol. Cancer Res 7 (2009): 1861-1870-   Er, T. K. et al., J Mol. Med. (Berl) (2016)-   Erb, H. H. et al., Endocr. Relat Cancer 20 (2013): 677-689-   Erdogan, E. et al., Clin Cancer Res 15 (2009): 1527-1533-   Erenpreisa, J. et al., Exp. Cell Res 315 (2009): 2593-2603-   Escobar-Hoyos, L. F. et al., Mod. Pathol. 27 (2014): 621-630-   Esseghir, S. et al., J Pathol. 210 (2006): 420-430-   Estrella, J. S. et al., Pancreas 43 (2014): 996-1002-   Ettahar, A. et al., Cell Rep. 4 (2013): 530-541-   Evans, T. J. et al., PLoS. One. 9 (2014): e110255-   Exertier, P. et al., Oncotarget. 4 (2013): 2302-2316-   Ezponda, T. et al., Oncogene 32 (2013): 2882-2890-   Fackler, M. et al., FEBS J 281 (2014): 2123-2135-   Fagin, J. A., Mol. Endocrinol. 16 (2002): 903-911-   Fairfield, K. M. et al., Int. J Cancer 110 (2004): 271-277-   Falk, K. et al., Nature 351 (1991): 290-296-   Falvella, F. S. et al., Oncogene 27 (2008): 3761-3764-   Fan, J. et al., Clin Cancer Res 17 (2011): 2908-2918-   Fan, M. et al., Int. J Clin Exp. Pathol. 7 (2014): 6768-6775-   Fang, H. Y. et al., Hum. Pathol. 43 (2012): 105-114-   Fang, K. P. et al., Asian Pac. J Cancer Prev. 15 (2014): 2655-2661-   Fang, Z. et al., J Biol Chem 288 (2013): 7918-7929-   Faried, L. S. et al., Mol. Carcinog 47 (2008): 446-457-   Faried, L. S. et al., Oncol Rep. 16 (2006): 57-63-   Faronato, M. et al., Oncotarget. (2015)-   Fasso, M. et al., Proc. Natl. Acad. Sci. U.S.A 105 (2008): 3509-3514-   Feldmann, G. et al., Cancer Res 70 (2010): 4460-4469-   Feng, H. et al., J Clin Invest 124 (2014a): 3741-3756-   Feng, M. et al., J Clin Invest 124 (2014b): 5291-5304-   Feng, X. et al., Neoplasma 62 (2015a): 592-601-   Feng, Y. et al., Sci. Rep. 5 (2015b): 9429-   Fernandez-Calotti, P. X. et al., Haematologica 97 (2012): 943-951-   Fernandez-Nogueira, P. et al., Oncotarget. 7 (2016): 5313-5326-   Ferreira-da-Silva, A. et al., PLoS. One. 10 (2015): e0122308-   Ferrero, S. et al., Histol. Histopathol. 30 (2015): 473-478-   Fevre-Montange, M. et al., Int. J Oncol 35 (2009): 1395-1407-   Fevre-Montange, M. et al., J Neuropathol. Exp. Neurol. 65 (2006):    675-684-   Fitzgerald, J. et al., FEBS Lett. 517 (2002): 61-66-   Fluge, O. et al., Thyroid 16 (2006): 161-175-   Fokas, E. et al., Cell Death. Dis. 3 (2012): e441-   Folgiero, V. et al., Oncotarget. 5 (2014): 2052-2064-   Fong, L. et al., Proc. Natl. Acad. Sci. U.S.A 98 (2001): 8809-8814-   Fortschegger, K. et al., Mol. Cancer Res 12 (2014): 595-606-   Fraga, M. F. et al., Cancer Res 68 (2008): 4116-4122-   Frasor, J. et al., Mol. Cell Endocrinol. 418 Pt 3 (2015): 235-239-   Frias, C. et al., Lung Cancer 60 (2008): 416-425-   Fry, A. M. et al., J Cell Sci. 125 (2012): 4423-4433-   Fu, A. et al., Mol. Carcinog 51 (2012): 923-929-   Fu, D. Y. et al., Tumour. Biol (2015)-   Fu, J. et al., Cancer Sci. 104 (2013a): 508-515-   Fu, M. et al., Int. J Clin Exp. Pathol. 6 (2013b): 2185-2191-   Fu, M. et al., Int. J Clin Exp. Pathol. 6 (2013c): 2515-2522-   Fu, Z. et al., Breast Cancer Res Treat. 127 (2011): 265-271-   Fujimura, K. et al., Clin Chim. Acta 430 (2014): 48-54-   Fujitomo, T. et al., Cancer Res 72 (2012): 4110-4118-   Fujiuchi, N. et al., J Biol Chem 279 (2004): 20339-20344-   Fukasawa, M. et al., J Hum. Genet. 51 (2006): 368-374-   Fukushima, Y. et al., Eur. J Cancer 35 (1999): 935-938-   Fuqua, S. A. et al., Breast Cancer Res Treat. 144 (2014): 11-19-   Furukawa, T. et al., Sci. Rep. 1 (2011): 161-   Furuta, J. et al., Cancer Res 66 (2006): 6080-6086-   Gaba, R. C. et al., J Vasc. Interv. Radiol. 26 (2015): 723-732-   Gabrilovich, D. I. et al., Nat Med. 2 (1996): 1096-1103-   Galamb, O. et al., Cell Oncol 31 (2009): 19-29-   Gallmeier, E. et al., Gastroenterology 130 (2006): 2145-2154-   Gantsev, S. K. et al., Biomed. Pharmacother. 67 (2013): 363-366-   Gao, F. et al., Biochem. Biophys. Res Commun. 431 (2013): 610-616-   Gao, J. et al., Acta Oncol 47 (2008): 372-378-   Gao, W. et al., BMC. Cancer 15 (2015): 367-   Gao, Y. B. et al., Nat Genet. 46 (2014): 1097-1102-   Gao, Z. et al., Biochem. Biophys. Res Commun. 407 (2011): 271-276-   Garcia-Baquero, R. et al., Tumour. Biol. 35 (2014): 5777-5786-   Garritano, S. et al., Oncogenesis. 2 (2013): e54-   Gattinoni, L. et al., Nat Rev. Immunol 6 (2006): 383-393-   Gatza, M. L. et al., Nat Genet. 46 (2014): 1051-1059-   Gaudineau, B. et al., J Cell Sci. 125 (2012): 4475-4486-   Ge, G. et al., Tumour. Biol (2015)-   Geiger, T. R. et al., PLoS. One. 9 (2014): e111813-   Gelebart, P. et al., J Biol Chem 277 (2002): 26310-26320-   Gelsi-Boyer, V. et al., Br. J Haematol. 145 (2009): 788-800-   Gentile, M. et al., Oncogene 20 (2001): 7753-7760-   Geoffroy-Perez, B. et al., Int. J Cancer 93 (2001): 288-293-   Georgiou, G. K. et al., World J Surg. Oncol 11 (2013): 213-   Ghosh, S. et al., Int. J Cancer 123 (2008): 2594-2604-   Gibbs, D. C. et al., Cancer Epidemiol. Biomarkers Prev. 24 (2015):    992-997-   Gil-Henn, H. et al., Oncogene 32 (2013): 2622-2630-   Gilling, C. E. et al., Br. J Haematol. 158 (2012): 216-231-   Giuliano, C. J. et al., Biochim. Biophys. Acta 1731 (2005): 48-56-   Glaser, R. et al., PLoS. One. 6 (2011): e25160-   Gnjatic, S. et al., Proc Natl. Acad. Sci. U.S.A 100 (2003):    8862-8867-   Godkin, A. et al., Int. Immunol 9 (1997): 905-911-   Going, J. J. et al., Gut 50 (2002): 373-377-   Gold, D. V. et al., Int. J Clin Exp. Pathol. 4 (2010): 1-12-   Goldenson, B. et al., Oncogene 34 (2015): 537-545-   Gong, X. et al., PLoS. One. 7 (2012): e37137-   Gonzalez, M. A. et al., J Clin Oncol 21 (2003): 4306-4313-   Goodman, S. L. et al., Biol Open. 1 (2012): 329-340-   Goswami, A. et al., Mol. Cell 20 (2005): 33-44-   Goto, Y. et al., J Invest Dermatol. 130 (2010): 221-229-   Gou, W. F. et al., Oncol Rep. 31 (2014): 232-240-   Govindaraj, V. et al., Horm. Mol. Biol Clin Investig. 9 (2012):    173-178-   Goyal, P. et al., PLoS. One. 6 (2011): e16249-   Grady, W. M., Cancer Metastasis Rev 23 (2004): 11-27-   Graff, L. et al., Cancer Res 61 (2001): 2138-2144-   Grant, R. C. et al., Hum. Genomics 7 (2013): 11-   Green, M. R. et al., Molecular Cloning, A Laboratory Manual 4th    (2012)-   Greenfield, E. A., Antibodies: A Laboratory Manual 2nd (2014)-   Greif, P. A. et al., Leukemia 25 (2011): 821-827-   Greuber, E. K. et al., Nat Rev Cancer 13 (2013): 559-571-   Grieb, B. C. et al., Mol. Cancer Res 12 (2014): 1216-1224-   Grimm, M. et al., BMC. Cancer 13 (2013): 569-   Grimmig, T. et al., Int. J Oncol 47 (2015): 857-866-   Grinberg-Rashi, H. et al., Clin Cancer Res 15 (2009): 1755-1761-   Gronnier, C. et al., Biochim. Biophys. Acta 1843 (2014): 2432-2437-   Groth-Pedersen, L. et al., PLoS. One. 7 (2012): e45381-   Gruel, N. et al., Breast Cancer Res 16 (2014): R46-   Grumati, P. et al., Cancer Discov 4 (2014): 394-396-   Gu, X. H. et al., Zhonghua Fu Chan Ke. Za Zhi. 44 (2009): 754-759-   Gu, Y. et al., Mol. Carcinog 55 (2016): 292-299-   Guan, G. et al., Arch. Biochem. Biophys. 417 (2003): 251-259-   Guan, X. et al., Carcinogenesis 34 (2013): 812-817-   Gueddari, N. et al., Biochimie 75 (1993): 811-819-   Guerreiro, A. S. et al., Mol. Cancer Res 9 (2011): 925-935-   Guerrero, J. A. et al., Blood 124 (2014): 3624-3635-   Guerrero-Preston, R. et al., Oncol Rep. 32 (2014): 505-512-   Guin, S. et al., J Natl. Cancer Inst. 106 (2014)-   Guirado, M. et al., Hum. Immunol. 73 (2012): 668-672-   Gultekin, Y. et al., J Innate. Immun. 7 (2015): 25-36-   Guo, F. et al., Mol. Biol Rep. 37 (2010): 3819-3825-   Guo, G. et al., Tumour. Biol 35 (2014): 4017-4022-   Guo, J. T. et al., Zhonghua Zhong. Liu Za Zhi. 31 (2009): 528-531-   Guo, S. et al., Drug Des Devel. Ther. 7 (2013): 1259-1271-   Guo, W. et al., J Mol. Biol 412 (2011): 365-378-   Guo, X. et al., Tumour. Biol 36 (2015): 1711-1720-   Gust, K. M. et al., Neoplasia. 11 (2009): 956-963-   Gutierrez, M. L. et al., PLoS. One. 6 (2011): e22315-   Gutierrez-Camino, A. et al., Pediatr. Res 75 (2014): 767-773-   Guyonnet, Duperat, V et al., Biochem. J 305 (Pt 1) (1995): 211-219-   Gylfe, A. E. et al., Int. J Cancer 127 (2010): 2974-2980-   Hagenbuchner, J. et al., Front Physiol 4 (2013): 147-   Haidar, A. et al., Am. J Case. Rep. 16 (2015): 87-94-   Halama, N. et al., Int. J Oncol 31 (2007): 205-210-   Hall, C. L. et al., J Neurooncol. 26 (1995): 221-229-   Hall, C. L. et al., Cell 82 (1995): 19-26-   Halldorsdottir, A. M. et al., Am. J Hematol. 87 (2012): 361-367-   Hammam, O. et al., J Egypt. Soc. Parasitol. 44 (2014): 733-740-   Han, J. C. et al., World J Surg. Oncol 13 (2015a): 5-   Han, L. L. et al., Oncol Rep. 31 (2014): 2569-2578-   Han, Y. et al., Cancer 119 (2013): 3436-3445-   Han, Z. et al., Oncotarget. 6 (2015b): 13149-13163-   Hansen-Petrik, M. B. et al., Cancer Lett. 175 (2002): 157-163-   Hao, J. et al., Oncol Lett. 9 (2015): 2525-2533-   Haque, M. A. et al., J Exp. Med. 195 (2002): 1267-1277-   Haridas, D. et al., FASEB J 28 (2014): 4183-4199-   Harken, Jensen C. et al., Tumour. Biol 20 (1999): 256-262-   Hartmann, T. B. et al., Int. J Cancer 114 (2005): 88-93-   Hasegawa, H. et al., Arch. Pathol. Lab Med. 122 (1998): 551-554-   Hashimoto, T. et al., FEBS J 277 (2010): 4888-4900-   Hast, B. E. et al., Cancer Res 73 (2013): 2199-2210-   Hatfield, K. J. et al., Expert. Opin. Ther. Targets. 18 (2014):    1237-1251-   Hayama, S. et al., Cancer Res 67 (2007): 4113-4122-   Hayashi, H. et al., Int. J Cancer 126 (2010): 2563-2574-   Hayashi, J. et al., Int. J Oncol 21 (2002): 847-850-   Hayashi, S. I. et al., Endocr. Relat Cancer 10 (2003): 193-202-   Hayatsu, N. et al., Biochem. Biophys. Res Commun. 368 (2008):    217-222-   Hazelett, C. C. et al., PLoS. One. 7 (2012): e39602-   He, D. et al., Biomed. Pharmacother. 74 (2015): 164-168-   He, H. et al., J Clin Endocrinol. Metab 98 (2013): E973-E980-   He, J. et al., Cancer Biol Ther. 6 (2007): 76-82-   He, Y. et al., Mol Carcinog. (2014)-   Hedrick, E. D. et al., J Mol. Signal. 8 (2013): 10-   Heeboll, S. et al., Histol. Histopathol. 23 (2008): 1069-1076-   Hegyi, K. et al., Pathobiology 79 (2012): 314-322-   Heidenblad, M. et al., BMC. Med. Genomics 1 (2008): 3-   Heim, S. et al., In Vivo 19 (2005): 583-590-   Heimerl, S. et al., Melanoma Res 17 (2007): 265-273-   Hellerbrand, C. et al., Carcinogenesis 27 (2006): 64-72-   Hellwinkel, O. J. et al., Prostate Cancer Prostatic. Dis. 14 (2011):    38-45-   Hemminger, J. A. et al., Mod. Pathol. 27 (2014): 1238-1245-   Hennard, C. et al., J Pathol. 209 (2006): 430-435-   Hennig, E. E. et al., J Mol. Med. (Berl) 90 (2012): 447-456-   Hickinson, D. M. et al., Clin Transl. Sci. 2 (2009): 183-192-   Hider, J. L. et al., BMC. Evol. Biol. 13 (2013): 150-   Hinrichsen, I. et al., PLoS. One. 9 (2014): e84453-   Hirota, Y. et al., Nucleic Acids Res 28 (2000): 917-924-   Hlavac, V. et al., Pharmacogenomics. 14 (2013): 515-529-   Hlavata, I. et al., Mutagenesis 27 (2012): 187-196-   Ho, M. et al., Clin Cancer Res 13 (2007): 1571-1575-   Hodi, F. S. et al., Proc. Natl. Acad. Sci. U.S.A 99 (2002):    6919-6924-   Hodson, I. et al., Int. J Oncol 23 (2003): 991-999-   Hoei-Hansen, C. E. et al., Clin Cancer Res 10 (2004): 8521-8530-   Hoellein, A. et al., J Cancer Res Clin Oncol 136 (2010): 403-410-   Hoff, A. M. et al., Oncotarget. (2015)-   Holla, V. R. et al., J Biol Chem 281 (2006): 2676-2682-   Holleman, A. et al., Blood 107 (2006): 769-776-   Holm, C. et al., Leuk. Res 30 (2006): 254-261-   Holzmann, K. et al., Cancer Res 64 (2004): 4428-4433-   Hong, J. et al., Biomed. Res Int. 2013 (2013): 454085-   Honore, B. et al., Oncogene 21 (2002): 1123-1129-   Hoque, M. O. et al., Cancer Res 68 (2008): 2661-2670-   Horani, A. et al., Am J Hum. Genet. 91 (2012): 685-693-   Horejsi, Z. et al., Mol. Cell 39 (2010): 839-850-   Horst, B. et al., Am. J Pathol. 174 (2009): 1524-1533-   Hosseini, M., Pol. J Pathol. 64 (2013): 191-195-   Hosseini, S. et al., Clin Lab 61 (2015): 475-480-   Hou, G. et al., Cancer Lett. 253 (2007): 236-248-   Hou, J. et al., Mol. Oncol 9 (2015): 1312-1323-   Hou, X. et al., Ann. Surg. Oncol 21 (2014): 3891-3899-   Hou, Y. et al., Med. Oncol 29 (2012): 3498-3503-   Hour, T. C. et al., Int. J Biol Markers 24 (2009): 171-178-   Hovnanian, A., Subcell. Biochem. 45 (2007): 337-363-   Hsu, P. K. et al., J Gastroenterol. 49 (2014): 1231-1240-   Hsu, W. H. et al., PLoS. One. 10 (2015): e0121298-   Hu, H. et al., Oncol Lett. 10 (2015): 268-272-   Hu, J. et al., Exp. Biol Med. (Maywood.) 239 (2014): 423-429-   Hu, S. et al., Pediatr. Hematol. Oncol 28 (2011): 140-146-   Hua, C. et al., BMC. Cancer 14 (2014): 526-   Huang, C. et al., Cell Biol Int. 32 (2008): 1081-1090-   Huang, H. et al., Clin Cancer Res 11 (2005a): 4357-4364-   Huang, H. et al., Beijing Da. Xue. Xue. Bao. 46 (2014a): 183-189-   Huang, H. et al., Int. J Oncol 38 (2011): 1557-1564-   Huang, L. N. et al., Clin Chim. Acta 413 (2012): 663-668-   Huang, X. et al., APMIS 122 (2014b): 1070-1079-   Huang, Y. et al., Int. J Mol. Sci. 15 (2014c): 18148-18161-   Huang, Y. et al., Oncogene 24 (2005b): 3819-3829-   Huang, Y. et al., Oncotarget. 5 (2014d): 6734-6745-   Hudlebusch, H. R. et al., Clin Cancer Res 17 (2011): 2919-2933-   Hudson, J. et al., Exp. Mol. Pathol. 95 (2013): 62-67-   Hui, L. et al., Oncol Rep. 34 (2015): 2627-2635-   Hummerich, L. et al., Oncogene 25 (2006): 111-121-   Hunecke, D. et al., J Pathol. 228 (2012): 520-533-   Hungermann, D. et al., J Pathol. 224 (2011): 517-528-   Hunter, S. M. et al., Oncotarget. 6 (2015): 37663-37677-   Hussein, Y. M. et al., Med. Oncol 29 (2012): 3055-3062-   Huynh, H. et al., Mol. Cancer Ther. 14 (2015): 1224-1235-   Hwang, C. F. et al., PLoS. One. 8 (2013): e84218-   Hwang, J. M. et al., Mol. Cell Biochem. 327 (2009): 135-144-   Hwang, M. L. et al., J Immunol. 179 (2007): 5829-5838-   Iacovazzi, P. A. et al., Immunopharmacol. Immunotoxicol. 32 (2010):    160-164-   Iakovlev, V. et al., Cancer Epidemiol. Biomarkers Prev. 21 (2012):    1135-1142-   Ibragimova, I. et al., Cancer Prev. Res (Phila) 3 (2010): 1084-1092-   Ida-Yonemochi, H. et al., Mod. Pathol. 25 (2012): 784-794-   Idbaih, A. et al., J Neurooncol. 90 (2008): 133-140-   Ide, H. et al., Biochem. Biophys. Res Commun. 369 (2008): 292-296-   Ii, M. et al., Exp. Biol. Med. (Maywood.) 231 (2006): 20-27-   Iio, A. et al., Biochim. Biophys. Acta 1829 (2013): 1102-1110-   Ijichi, N. et al., J Steroid Biochem. Mol. Biol 123 (2011): 1-7-   Ikeda, R. et al., Int. J Oncol 38 (2011): 513-519-   Ikonomov, O. C. et al., Biochem. Biophys. Res Commun. 440 (2013):    342-347-   Ilboudo, A. et al., BMC. Cancer 14 (2014): 7-   Illemann, M. et al., Cancer Med. 3 (2014): 855-864-   Imai, K. et al., Br. J Cancer 104 (2011): 300-307-   Imoto, I. et al., Biochem. Biophys. Res Commun. 286 (2001): 559-565-   Inamoto, T. et al., Mol. Cancer Ther. 7 (2008): 3825-3833-   Ino, K. et al., Clin Cancer Res 14 (2008): 2310-2317-   Inoda, S. et al., Am. J Pathol. 178 (2011a): 1805-1813-   Inoda, S. et al., J Immunother. 32 (2009): 474-485-   Inoda, S. et al., Exp. Mol. Pathol. 90 (2011 b): 55-60-   Ioachim, H. L. et al., Am. J Surg. Pathol. 20 (1996): 64-71-   Iscan, M. et al., Breast Cancer Res Treat. 70 (2001): 47-54-   Ishida, T. et al., Leukemia 20 (2006): 2162-2168-   Ishigami, S. et al., Cancer Lett. 168 (2001): 87-91-   Ishigami, S. et al., BMC. Cancer 11 (2011): 106-   Ishikawa, S. et al., J Exp. Clin Cancer Res 22 (2003): 299-306-   Issaq, S. H. et al., Mol. Cancer Res 8 (2010): 223-231-   Ito, K. et al., Protein Cell 2 (2011): 755-763-   Ito, M. et al., Jpn. J Clin Oncol 36 (2006): 116-120-   Ito, Y. et al., Oncology 59 (2000): 68-74-   Itoh, G. et al., Cancer Sci. 104 (2013): 871-879-   Ivyna Bong, P. N. et al., Mol. Cytogenet. 7 (2014): 24-   Iwakuma, T. et al., Cancer Metastasis Rev 31 (2012): 633-640-   Iwanaga, K. et al., Cancer Lett. 202 (2003): 71-79-   Izykowska, K. et al., Eur. J Haematol. 93 (2014): 143-149-   Jaaskelainen, T. et al., Mol. Cell Endocrinol. 350 (2012): 87-98-   Jackson, R. S. et al., Cell Cycle 6 (2007): 95-103-   Jacob, F. et al., BMC. Mol. Biol 15 (2014): 24-   Jacques, C. et al., J Clin Endocrinol. Metab 90 (2005): 2314-2320-   Jager, D. et al., Cancer Res 60 (2000): 3584-3591-   Jaggi, M. et al., Prostate 66 (2006): 193-199-   Jais, J. P. et al., Leukemia 22 (2008): 1917-1924-   Jakobsson, J. et al., Pharmacogenomics. J 4 (2004): 245-250-   Jalava, S. E. et al., Int. J Cancer 124 (2009): 95-102-   Jang, S. G. et al., BMC. Cancer 7 (2007): 16-   Januchowski, R. et al., Biomed. Pharmacother. 67 (2013): 240-245-   Janus, J. R. et al., Laryngoscope 121 (2011): 2598-2603-   Jayaram, H. N. et al., Curr. Med. Chem 6 (1999): 561-574-   Jayarama, S. et al., J Cell Biochem. 115 (2014): 261-270-   Jeffery, J. et al., FASEB J 29 (2015a): 1999-2009-   Jeffery, J. et al., Oncogene (2015b)-   Jensen, C. H. et al., Eur. J Biochem. 225 (1994): 83-92-   Jensen, S. A. et al., Proc. Natl. Acad. Sci. U.S.A 111 (2014):    5682-5687-   Jessie, K. et al., Electrophoresis 34 (2013): 2495-2502-   Ji, P. et al., Oncogene 24 (2005): 2739-2744-   Jia, D. et al., Hepatology 54 (2011): 1227-1236-   Jiang, J. H. et al., Ai. Zheng. 23 (2004): 672-677-   Jiang, J. H. et al., Hepatology 59 (2014a): 2216-2227-   Jiang, N. et al., J Biol Chem 278 (2003): 21678-21684-   Jiang, P. et al., Mol. Med. Rep. 9 (2014b): 2347-2351-   Jiang, Q. et al., Histopathology 64 (2014c): 722-730-   Jiao, X. et al., Genes Chromosomes. Cancer 51 (2012): 480-489-   Jin, J. K. et al., Oncogene 34 (2015): 1811-1821-   Jinawath, N. et al., Oncogene 28 (2009): 1941-1948-   Jing, Z. et al., J Immunol. 185 (2010): 6719-6727-   Jinushi, M. et al., Cancer Res 68 (2008): 8889-8898-   Johansson, P. et al., J Biol Chem 289 (2014): 18514-18525-   Johnson, D. P. et al., Oncotarget. 6 (2015): 4863-4887-   Joosse, S. A. et al., Clin Cancer Res 18 (2012): 993-1003-   Jose-Eneriz, E. S. et al., Br. J Haematol. 142 (2008): 571-582-   Joshi, A. D. et al., Clin Cancer Res 13 (2007): 5295-5304-   Joshi, S. et al., BMC. Cancer 15 (2015): 546-   Judson, H. et al., Hum. Genet. 106 (2000): 406-413-   Junes-Gill, K. S. et al., J Neurooncol. 102 (2011): 197-211-   Junes-Gill, K. S. et al., BMC. Cancer 14 (2014): 920-   Jung, G. et al., Proc Natl Acad Sci USA 84 (1987): 4611-4615-   Jung, H. C. et al., Life Sci. 77 (2005): 1249-1262-   Jung, W. Y. et al., Appl. Immunohistochem. Mol. Morphol. 22 (2014):    652-657-   Juszczynski, P. et al., Mol. Cell Biol 26 (2006): 5348-5359-   Kabbage, M. et al., J Biomed. Biotechnol. 2008 (2008): 564127-   Kaizuka, T. et al., J Biol Chem 285 (2010): 20109-20116-   Kalin, T. V. et al., Cancer Res 66 (2006): 1712-1720-   Kalinichenko, V. V. et al., Genes Dev. 18 (2004): 830-850-   Kalinina, T. et al., BMC. Cancer 10 (2010): 295-   Kalogeropoulou, M. et al., Mol. Cancer Res 8 (2010): 554-568-   Kamatani, N. et al., Cancer Res 40 (1980): 4178-4182-   Kamino, H. et al., Cancer Genet. 204 (2011): 382-391-   Kamiyama, S. et al., Glycobiology 21 (2011): 235-246-   Kanda, A. et al., Oncogene 24 (2005): 7266-7272-   Kandoth, C. et al., Nature 497 (2013): 67-73-   Kang, B. W. et al., PLoS. One. 10 (2015a): e0119649-   Kang, G. et al., PLoS. One. 8 (2013): e82770-   Kang, J. K. et al., Int. J Oncol 16 (2000): 1159-1163-   Kang, J. M. et al., Cancer Res 75 (2015b): 3087-3097-   Kang, J. U. et al., Int. J Oncol 37 (2010): 327-335-   Kang, J. U. et al., Cancer Genet. Cytogenet. 182 (2008a): 1-11-   Kang, M. J. et al., Prostate 72 (2012): 1351-1358-   Kang, S. K. et al., Am. J Pathol. 173 (2008b): 518-525-   Kang, X. et al., Oncogene 28 (2009): 565-574-   Kapoor, A. et al., Nature 468 (2010): 1105-1109-   Karahatay, S. et al., Cancer Lett. 256 (2007): 101-111-   Karbowniczek, M. et al., J Invest Dermatol. 128 (2008): 980-987-   Karess, R. E. et al., Int. Rev Cell Mol. Biol 306 (2013): 223-273-   Karim, H. et al., Biochem. Biophys. Res Commun. 411 (2011): 156-161-   Karlsson, E. et al., Breast Cancer Res Treat. 153 (2015): 31-40-   Karytinos, A. et al., J Biol Chem 284 (2009): 17775-17782-   Kashuba, V. et al., Int. J Mol. Sci. 13 (2012): 13352-13377-   Kashyap, V. et al., Mol Oncol 7 (2013): 555-566-   Kassambara, A. et al., Biochem. Biophys. Res Commun. 379 (2009):    840-845-   Kato, I. et al., Pathol. Int. 59 (2009): 38-43-   Kato, S. et al., Int. J Oncol 29 (2006): 33-40-   Katoh, M. et al., Int. J Oncol 25 (2004): 1495-1500-   Katoh, Y. et al., Int. J Mol. Med. 18 (2006): 523-528-   Katz, T. A. et al., Breast Cancer Res Treat. 146 (2014): 99-108-   Kaufmann, M. et al., Curr. Top. Microbiol. Immunol. 384 (2015):    167-188-   Kaur, H. et al., PLoS. One. 7 (2012): e50249-   Kawagoe, H. et al., Cancer Res 64 (2004): 6091-6100-   Kawahara, R. et al., Proteomics. 16 (2016): 159-173-   Kawakami, K. et al., Int. J Oncol (2015)-   Kawakami, M. et al., Cancer Sci. 104 (2013): 1447-1454-   Kaynar, H. et al., Cancer Lett. 227 (2005): 133-139-   Kazma, R. et al., Carcinogenesis 33 (2012): 1059-1064-   Ke, J. Y. et al., J Zhejiang. Univ Sci. B 15 (2014a): 1032-1038-   Ke, R. H. et al., J Neurooncol. 118 (2014b): 369-376-   Kearns, P. R. et al., Br. J Haematol. 120 (2003): 80-88-   Keng, V. W. et al., Nat Biotechnol. 27 (2009): 264-274-   Kerley-Hamilton, J. S. et al., Oncogene 24 (2005): 6090-6100-   Kesari, M. V. et al., Indian J Gastroenterol. 34 (2015): 63-67-   Khan, J. et al., PLoS. One. 6 (2011): e26512-   Khodarev, N. N. et al., Cancer Res 69 (2009): 2833-2837-   Kibbe, A. H., Handbook of Pharmaceutical Excipients rd (2000)-   Kiessling, A. et al., Oncogene 28 (2009): 2606-2620-   Kikuchi, Y. et al., Front Genet. 4 (2013): 271-   Killian, A. et al., Genes Chromosomes. Cancer 45 (2006): 874-881-   Kim, B. H. et al., Ann. Surg. Oncol 21 (2014a): 2020-2027-   Kim, D. H., Yonsei Med. J 48 (2007): 694-700-   Kim, D. S. et al., J Proteome. Res 9 (2010): 3710-3719-   Kim, H. E. et al., PLoS. One. 7 (2012a): e43223-   Kim, H. J. et al., J Proteome. Res 8 (2009a): 1368-1379-   Kim, H. N. et al., Am. J Hematol. 82 (2007): 798-801-   Kim, I. M. et al., Cancer Res 66 (2006): 2153-2161-   Kim, J. et al., Genes Chromosomes. Cancer 54 (2015a): 681-691-   Kim, J. C. et al., Int. J Radiat. Oncol Biol Phys. 86 (2013a):    350-357-   Kim, J. C. et al., World J Gastroenterol. 14 (2008a): 6662-6672-   Kim, J. H. et al., Cancer 85 (1999): 546-553-   Kim, J. H. et al., BMB. Rep. 44 (2011a): 523-528-   Kim, J. W. et al., Int. J Oncol 35 (2009b): 129-137-   Kim, K. et al., Mol. Cell 52 (2013b): 459-467-   Kim, M. et al., Mol Cancer Res 6 (2008b): 222-230-   Kim, M. S. et al., Oncogene 27 (2008c): 3624-3634-   Kim, M. S. et al., Histopathology 58 (2011 b): 660-668-   Kim, R. et al., PLoS. One. 10 (2015b): e0126670-   Kim, S. H. et al., Investig. Clin Urol. 57 (2016): 63-72-   Kim, S. J. et al., Acta Haematol. 120 (2008d): 211-216-   Kim, S. J. et al., Mol. Carcinog 54 (2015c): 1748-1757-   Kim, S. M. et al., Int. J Cancer 134 (2014b): 114-124-   Kim, S. W. et al., OMICS. 15 (2011c): 281-292-   Kim, S. W. et al., Blood 111 (2008e): 1644-1653-   Kim, Y. D. et al., Int. J Mol. Med. 29 (2012b): 656-662-   Kim, Y. W. et al., PLoS. One. 7 (2012c): e40960-   Kindt, N. et al., J Cancer Res Clin Oncol 140 (2014): 937-947-   Kinoshita, Y. et al., Am. J Pathol. 180 (2012): 375-389-   Kitange, G. J. et al., J Neurooncol. 100 (2010): 177-186-   Klatka, J. et al., Eur. Arch. Otorhinolaryngol. 270 (2013):    2683-2693-   Kleppe, M. et al., Nat Genet. 42 (2010): 530-535-   Kleppe, M. et al., Blood 117 (2011a): 7090-7098-   Kleppe, M. et al., Haematologica 96 (2011 b): 1723-1727-   Kleylein-Sohn, J. et al., J Cell Sci. 125 (2012): 5391-5402-   Knapp, P. et al., Prostaglandins Other Lipid Mediat. 92 (2010):    62-66-   Ko, H. W. et al., Dev. Cell 18 (2010): 237-247-   Kobayashi, H. et al., Biochem. Biophys. Res Commun. 467 (2015a):    121-127-   Kobayashi, M. et al., Lung Cancer 90 (2015b): 342-345-   Kobayashi, Y. et al., Placenta 34 (2013): 110-118-   Kocer, B. et al., Pathol. Int. 52 (2002): 470-477-   Kogo, R. et al., Int. J Oncol 39 (2011): 155-159-   Kohno, T. et al., Nat Med. 18 (2012): 375-377-   Kohrt, D. et al., Cell Cycle 13 (2014): 62-71-   Koike, K., Recent Results Cancer Res 193 (2014): 97-111-   Kokoglu, E. et al., Cancer Lett. 50 (1990): 179-181-   Kolb, T. M. et al., Toxicol. Sci. 88 (2005): 331-339-   Kollmann, K. et al., Cancer Cell 24 (2013): 167-181-   Kong, L. et al., Shanghai Kou Qiang. Yi. Xue. 24 (2015): 89-93-   Koo, G. B. et al., Cell Res 25 (2015a): 707-725-   Koo, S. et al., Anticancer Res 35 (2015b): 3209-3215-   Koochekpour, S. et al., Asian J Androl 7 (2005a): 147-158-   Koochekpour, S. et al., Genes Chromosomes. Cancer 44 (2005b):    351-364-   Kordi Tamandani, D. M. et al., J Assist. Reprod. Genet. 26 (2009):    173-178-   Korosec, B. et al., Cancer Genet. Cytogenet. 171 (2006): 105-111-   Korotayev, K. et al., Cell Signal. 20 (2008): 1221-1226-   Kortum, K. M. et al., Ann. Hematol. 94 (2015): 1205-1211-   Koshikawa, K. et al., Oncogene 21 (2002): 2822-2828-   Kozlowski, L. et al., Arch. Dermatol. Res 292 (2000): 68-71-   Kraemer, N. et al., Cell Mol Life Sci. 68 (2011): 1719-1736-   Kramer, M. et al., Biomed. Res Int. 2015 (2015): 208017-   Krieg, A. M., Nat Rev. Drug Discov. 5 (2006): 471-484-   Krona, C. et al., Oncogene 22 (2003): 2343-2351-   Kuang, S. Q. et al., Leukemia 22 (2008): 1529-1538-   Kuasne, H. et al., Clin Epigenetics. 7 (2015): 46-   Kubota, H. et al., Cell Stress. Chaperones. 15 (2010): 1003-1011-   Kudo, Y. et al., J Hepatol. 55 (2011): 1400-1408-   Kuhn, E. et al., Mod. Pathol. 27 (2014): 1014-1019-   Kulkarni, A. A. et al., Clin Cancer Res 15 (2009): 2417-2425-   Kumar, S. et al., Cell Death. Dis. 6 (2015): e1758-   Kumarakulasingham, M. et al., Clin Cancer Res 11 (2005): 3758-3765-   Kuo, I. Y. et al., Int. J Cancer 135 (2014): 563-573-   Kuo, S. J. et al., Oncol Rep. 24 (2010): 759-766-   Kuphal, S. et al., Oncogene 25 (2006): 103-110-   Kuppers, R. et al., J Clin Invest 111 (2003): 529-537-   Kuramitsu, Y. et al., Anticancer Res 31 (2011): 3331-3336-   Kurtovic-Kozaric, A. et al., Leukemia 29 (2015): 126-136-   Kuruma, H. et al., Am. J Pathol. 174 (2009): 2044-2050-   Kutikhin, A. G., Hum. Immunol. 72 (2011): 955-968-   Kuznetsova, E. B. et al., Mol. Biol. (Mosk) 41 (2007): 624-633-   Kwon, J. et al., Int J Oncol 43 (2013): 1523-1530-   La, Vecchia C., Eur. J Cancer Prev. 10 (2001): 125-129-   Labhart, P. et al., Proc. Natl. Acad. Sci. U.S.A 102 (2005):    1339-1344-   Laetsch, T. W. et al., Cell Death. Dis. 5 (2014): e1072-   Lage, H. et al., FEBS Lett. 494 (2001): 54-59-   Lagorce-Pages, C. et al., Virchows Arch. 444 (2004): 426-435-   Lai, J. M. et al., Methods Mol. Biol 623 (2010): 231-242-   Lai, M. T. et al., J Pathol. 224 (2011): 367-376-   Lake, S. L. et al., Invest Ophthalmol. Vis. Sci. 52 (2011):    5598-5604-   Lan, H. et al., Int. J Clin Exp. Med. 7 (2014): 665-672-   Lan, Q. et al., Eur. J Haematol. 85 (2010): 492-495-   Lane, J. et al., Int. J Mol. Med. 12 (2003): 253-257-   Langemeijer, S. M. et al., Cell Cycle 8 (2009): 4044-4048-   Lapointe, J. et al., Am. J Surg. Pathol. 32 (2008): 205-209-   Lapouge, G. et al., Cell Mol. Life Sci. 62 (2005): 53-64-   Lara, P. C. et al., Radiat. Oncol 6 (2011): 148-   Larkin, S. E. et al., Br. J Cancer 106 (2012): 157-165-   Laske, K. et al., Cancer Immunol. Res 1 (2013): 190-200-   Lau, L. F., Cell Mol. Life Sci. 68 (2011): 3149-3163-   Lau, Y. F. et al., Mol. Carcinog 27 (2000): 308-321-   Lauring, J. et al., Blood 111 (2008): 856-864-   Lazova, R. et al., Am. J Dermatopathol. 31 (2009): 177-181-   Leal, J. F. et al., Carcinogenesis 29 (2008): 2089-2095-   Ledet, E. M. et al., Prostate 73 (2013): 614-623-   Lee, B. H. et al., Cancer Res 73 (2013a): 1211-1218-   Lee, E. J. et al., Oncol Res 18 (2010): 401-408-   Lee, E. K. et al., Mol. Cell Biol 33 (2013b): 4422-4433-   Lee, J. H. et al., Ann. Surg. 249 (2009): 933-941-   Lee, M. J. et al., J Proteome. Res 13 (2014a): 4878-4888-   Lee, S. Y. et al., Eur. J Cancer 50 (2014b): 698-705-   Lee, T. J. et al., Mol. Cancer 3 (2004): 31-   Lee, Y. S. et al., Oncotarget. 6 (2015): 16449-16460-   Leong, H. S. et al., Cancer Res 73 (2013): 1591-1599-   Leong, S. R. et al., Mol. Pharm. 12 (2015): 1717-1729-   Levi, E. et al., Cancer Chemother. Pharmacol. 67 (2011): 1401-1413-   Levy, P. et al., Clin Cancer Res 13 (2007): 398-407-   Li, B. H. et al., Biochem. Biophys. Res Commun. 369 (2008a): 554-560-   Li, B. S. et al., Oncogene 34 (2015a): 2556-2565-   Li, C. F. et al., Oncotarget. 5 (2014a): 11428-11441-   Li, C. F. et al., BMC. Genomics 8 (2007): 92-   Li, C. M. et al., Am. J Pathol. 160 (2002): 2181-2190-   Li, H. et al., Neoplasia. 8 (2006): 568-577-   Li, J. et al., Zhonghua Bing. Li Xue. Za Zhi. 43 (2014b): 546-550-   Li, J. F. et al., Zhonghua Wei Chang Wai Ke. Za Zhi. 15 (2012a):    388-391-   Li, J. Y. et al., Chin Med. J (Engl.) 125 (2012b): 3526-3531-   Li, L. et al., Clin Cancer Res 19 (2013a): 4651-4661-   Li, L. et al., Pharmacogenet. Genomics 22 (2012c): 105-116-   Li, L. C. et al., Am. J Obstet. Gynecol. 205 (2011a): 362-25-   Li, M. et al., Clin Cancer Res 11 (2005): 1809-1814-   Li, N. et al., Biochem. Biophys. Res Commun. 455 (2014): 358-362-   Li, Q. et al., Mol. Biol Rep. 41 (2014c): 2409-2417-   Li, S. et al., J Huazhong. Univ Sci. Technolog. Med. Sci. 28    (2008b): 93-96-   Li, S. et al., Proc. Natl. Acad. Sci. U.S.A 111 (2014d): 6970-6975-   Li, T. et al., J Thorac. Oncol 7 (2012d): 448-452-   Li, W. et al., Cancer Cell Int. 15 (2015b): 17-   Li, W. et al., Med. Oncol 31 (2014e): 208-   Li, W. Q. et al., Carcinogenesis 34 (2013b): 1536-1542-   Li, X. et al., Curr. Protein Pept. Sci. 16 (2015c): 301-309-   Li, X. et al., Pancreas 40 (2011 b): 753-761-   Li, X. et al., BMC. Cancer 15 (2015d): 342-   Li, X. et al., Cancer Res (2016)-   Li, Y. et al., Cancer Genet. Cytogenet. 198 (2010): 97-106-   Li, Y. et al., Cancer Biol Ther. 16 (2015e): 1316-1322-   Li, Y. et al., Clin Cancer Res 17 (2011c): 3830-3840-   Li, Y. et al., Lung Cancer 80 (2013c): 91-98-   Li, Z. et al., Diagn. Pathol. 10 (2015f): 167-   Li, Z. et al., Nan. Fang Yi. Ke. Da. Xue. Xue. Bao. 33 (2013d):    1483-1488-   Lian, Z. et al., Cancer Biol Ther. 16 (2015): 750-755-   Liang, B. et al., Zhonghua Yi. Xue. Za Zhi. 95 (2015a): 408-411-   Liang, B. et al., Dig. Dis. Sci. 60 (2015b): 2360-2372-   Liang, H. et al., Genome Res 22 (2012a): 2120-2129-   Liang, Q. et al., Sci. Rep. 3 (2013): 2932-   Liang, X. S. et al., Int. J Cancer 130 (2012b): 2062-2066-   Liang, X. T. et al., J Gastroenterol. Hepatol. 26 (2011): 544-549-   Liang, Y. et al., BMC. Cancer 6 (2006): 97-   Liang, Y. et al., Proc. Natl. Acad. Sci. U.S.A 102 (2005): 5814-5819-   Liao, C. F. et al., J Exp. Clin Cancer Res 27 (2008): 15-   Liao, F. et al., Med. Oncol 27 (2010): 1219-1226-   Liao, Y. et al., BMC. Cancer 14 (2014a): 487-   Liao, Y. et al., PLoS. One. 9 (2014b): e99907-   Liddy, N. et al., Nat Med. 18 (2012): 980-987-   Lignitto, L. et al., Nat Commun. 4 (2013): 1822-   Lim, B. et al., Carcinogenesis 35 (2014): 1020-1027-   Lim, S. O. et al., Biochem. Biophys. Res Commun. 291 (2002):    1031-1037-   Lin, D. C. et al., Nat Genet. 46 (2014): 467-473-   Lin, F. et al., Cancer Biol Ther. 7 (2008a): 1669-1676-   Lin, H. S. et al., Arch. Otolaryngol. Head Neck Surg. 130 (2004):    311-316-   Lin, P. et al., Mol. Biol Rep. 38 (2011): 1741-1747-   Lin, P. H. et al., J Biomed. Sci. 22 (2015a): 44-   Lin, S. et al., RNA. Biol 12 (2015): 792-800-   Lin, W. Y. et al., Hum. Mol. Genet. 24 (2015b): 285-298-   Lin, Y. L. et al., Int. J Clin Exp. Pathol. 8 (2015c): 14257-14269-   Lin, Y. M. et al., Mol. Carcinog 47 (2008b): 925-933-   Lin, Y. W. et al., Oral Oncol 48 (2012): 629-635-   Lindberg, D. et al., Neuroendocrinology 86 (2007): 112-118-   Linder, N. et al., Gynecol. Oncol 124 (2012): 311-318-   Linder, N. et al., Clin Cancer Res 11 (2005): 4372-4381-   Ling, Z. Q. et al., Eur. J Surg. Oncol 38 (2012): 326-332-   Linge, A. et al., Invest Ophthalmol. Vis. Sci. 53 (2012): 4634-4643-   Lips, E. H. et al., BMC. Cancer 8 (2008): 314-   Lipson, D. et al., Nat Med. 18 (2012): 382-384-   Litvinov, I. V. et al., Clin. Cancer Res. 20 (2014a): 3799-3808-   Litvinov, I. V. et al., Oncoimmunology 3 (2014b): e970025-   Liu, B. et al., Biochem. Biophys. Res Commun. 293 (2002a): 1396-1404-   Liu, C. et al., Int. J Clin Exp. Pathol. 7 (2014a): 690-698-   Liu, D. et al., Oncotarget. 6 (2015a): 39211-39224-   Liu, D. Q. et al., Sci. Rep. 5 (2015b): 11955-   Liu, F. et al., Tumour. Biol 35 (2014b): 8685-8690-   Liu, J. et al., PLoS. One. 9 (2014c): e89340-   Liu, J. et al., Biochem. Biophys. Res Commun. 463 (2015c): 1230-1236-   Liu, J. F. et al., Cancer Cell Int. 13 (2013a): 41-   Liu, L. X. et al., World J Gastroenterol. 8 (2002b): 631-637-   Liu, L. X. et al., Oncol Rep. 10 (2003): 1771-1775-   Liu, L. Z. et al., Cancer Res 67 (2007): 6325-6332-   Liu, M. et al., Cancer Res 66 (2006): 3593-3602-   Liu, P. et al., J Natl. Cancer Inst. 100 (2008a): 1326-1330-   Liu, Q. et al., Prostate 73 (2013b): 1028-1037-   Liu, Q. et al., Med. Oncol 31 (2014d): 882-   Liu, R. et al., Proc. Natl. Acad. Sci. U.S.A 105 (2008b): 7570-7575-   Liu, R. et al., Oncotarget. 6 (2015d): 33456-33469-   Liu, S. Y. et al., Zhonghua Wai Ke. Za Zhi. 47 (2009a): 1732-1735-   Liu, W. et al., Ann. Surg. Oncol 21 Suppl 4 (2014e): S575-S583-   Liu, W. et al., J Biol. Chem. 279 (2004): 10167-10175-   Liu, W. et al., Mol. Clin Oncol 2 (2014f): 219-225-   Liu, X. et al., PLoS. One. 8 (2013c): e77367-   Liu, X. et al., Pathol. Res Pract. 210 (2014g): 256-263-   Liu, X. et al., Zhonghua Yi. Xue. Za Zhi. 94 (2014h): 2008-2012-   Liu, X. et al., Med. Oncol 30 (2013d): 735-   Liu, Y. et al., Cancer Res 69 (2009b): 7844-7850-   Liu, Y. et al., Asian Pac. J Cancer Prev. 16 (2015e): 2659-2664-   Liu, Y. et al., Int. J Clin Exp. Pathol. 7 (2014i): 5750-5761-   Liu, Y. X. et al., Oncol Lett. 4 (2012): 847-851-   Liu, Z. et al., Oncol Rep. 33 (2015f): 1908-1914-   Liu, Z. et al., BMC. Cancer 14 (2014j): 274-   Liu, Z. et al., Carcinogenesis 32 (2011): 1668-1674-   Ljunggren, H. G. et al., J Exp. Med. 162 (1985): 1745-1759-   Llopis, S. et al., BMC. Cancer 13 (2013): 139-   Lo, Y. W. et al., J Cell Mol. Med. 19 (2015): 744-759-   Long, Z. W. et al., Tumour. Biol. 35 (2014): 11415-11426-   Longenecker, B. M. et al., Ann N. Y. Acad. Sci. 690 (1993): 276-291-   Lonsdale, J., Nat. Genet. 45 (2013): 580-585-   Lopez-Cortes, A. et al., Am. J Med. Sci. 346 (2013): 447-454-   Lou, T. F. et al., Cancer Prev. Res (Phila) 9 (2016): 43-52-   Lozupone, F. et al., Oncogene (2015)-   Lu, C. et al., Mol. Cell Biochem. 312 (2008): 71-80-   Lu, C. et al., Dig. Dis. Sci. 58 (2013): 2713-2720-   Lu, J. et al., Oncol Rep. 32 (2014a): 2571-2579-   Lu, J. J. et al., Chin J Nat Med. 13 (2015): 673-679-   Lu, P. et al., PLoS. One. 9 (2014b): e88918-   Lu, X. et al., Mol. Cancer Ther. 3 (2004): 861-872-   Lu, X. et al., Clin Cancer Res 15 (2009): 3287-3296-   Lucas, S. et al., Int. J Cancer 87 (2000): 55-60-   Lucito, R. et al., Cancer Biol Ther. 6 (2007): 1592-1599-   Ludwig, A. et al., Anticancer Res 22 (2002): 3213-3221-   Lukas, T. J. et al., Proc. Natl. Acad. Sci. U.S.A 78 (1981):    2791-2795-   Luker, K. E. et al., Cancer Res 61 (2001): 6540-6547-   Luksch, H. et al., Anticancer Res 31 (2011): 3181-3192-   Lum, D. F. et al., Int. J Cancer 83 (1999): 162-166-   Lundblad, R. L., Chemical Reagents for Protein Modification 3rd    (2004)-   Luo, X. et al., J Clin Endocrinol. Metab 94 (2009): 4533-4539-   Lv, T. et al., PLoS. One. 7 (2012): e35065-   Lyng, H. et al., BMC. Genomics 7 (2006): 268-   Ma, G. F. et al., Eur. Rev. Med. Pharmacol. Sci. 19 (2015): 578-585-   Ma, Q. et al., Biochem. Biophys. Res Commun. 454 (2014): 157-161-   MacDonald, G. et al., Sci. Signal. 7 (2014): ra56-   MacDonald, T. J. et al., Methods Mol. Biol 377 (2007): 203-222-   Mackay, C. et al., Cancer Res 74 (2014): 2246-2257-   Madden, S. F. et al., Mol. Cancer 13 (2014): 241-   Madhavan, S. et al., J Exp. Clin Cancer Res 34 (2015): 45-   Magold, A. I. et al., PLoS. One. 4 (2009): e6952-   Mahmood, S. F. et al., Carcinogenesis 35 (2014): 670-682-   Makkinje, A. et al., Cell Signal. 21 (2009): 1423-1435-   Malta-Vacas, J. et al., Clin Chem Lab Med. 47 (2009): 427-431-   Malumbres, M. et al., Curr. Opin. Genet. Dev. 17 (2007): 60-65-   Man, T. K. et al., BMC. Cancer 4 (2004): 45-   Mang, J. et al., Transl. Oncol 8 (2015): 487-496-   Mangs, A. H. et al., Int. J Biochem. Cell Biol 40 (2008): 2353-2357-   Mano, Y. et al., Cancer Sci. 98 (2007): 1902-1913-   Mantia-Smaldone, G. M. et al., Hum. Vaccin. Immunother. 8 (2012):    1179-1191-   Mao, J. et al., Cancer Sci. 99 (2008): 2120-2127-   Mao, P. et al., J Biol Chem 286 (2011): 19381-19391-   Mao, P. et al., PLoS. One. 8 (2013a): e81803-   Mao, Y. et al., BMC. Cancer 13 (2013b): 498-   Marechal, R. et al., Clin Cancer Res 15 (2009): 2913-2919-   Marian, C. et al., Eur. J Clin Nutr. 65 (2011): 683-689-   Marini, F. et al., J Biol Chem 277 (2002): 8716-8723-   Markt, S. C. et al., Cancer Causes Control 26 (2015): 25-33-   Marlow, L. A. et al., J Cell Sci. 125 (2012): 4253-4263-   Marmey, B. et al., Hum. Pathol. 37 (2006): 68-77-   Marques Filho, M. F. et al., Braz. J Otorhinolaryngol. 72 (2006):    25-30-   Martens-de Kemp, S. R. et al., Clin Cancer Res 19 (2013): 1994-2003-   Martin, L. et al., Oncogene 31 (2012): 4076-4084-   Martin, T. A. et al., J Cell Biochem. 105 (2008): 41-52-   Martin, T. A. et al., Methods Mol. Biol 762 (2011): 383-407-   Martin, T. D. et al., Mol. Cell 53 (2014): 209-220-   Martinez-Trillos, A. et al., Blood 123 (2014): 3790-3796-   Masuda, K. et al., Oncol Rep. 28 (2012): 1146-1152-   Masuda, T. A. et al., Clin Cancer Res 9 (2003): 5693-5698-   Masugi, Y. et al., Lab Invest 95 (2015): 308-319-   Matejcic, M. et al., PLoS. One. 6 (2011): e29366-   Mathew, M. et al., Apoptosis. 18 (2013): 882-895-   Matovina, M. et al., Gynecol. Oncol 113 (2009): 120-127-   Matsumoto, K. et al., Genes Cells 6 (2001): 1101-1111-   Matsumoto, N. et al., Leukemia 14 (2000): 1757-1765-   Matsuyama, A. et al., Virchows Arch. 459 (2011): 539-545-   Matsuyama, A. et al., Virchows Arch. 457 (2010): 577-583-   Matsuyama, R. et al., Cancer Sci. 107 (2016): 28-35-   Maurizio, E. et al., Mol. Cell Proteomics. 15 (2016): 109-123-   Maxwell, C. A. et al., J Cell Sci. 121 (2008): 925-932-   Mayne, M. et al., Eur. J Immunol. 34 (2004): 1217-1227-   Mazan-Mamczarz, K. et al., PLoS. Genet. 10 (2014): el 004105-   Mazzoccoli, G. et al., Chronobiol. Int. 28 (2011): 841-851-   McCabe, K. E. et al., Cell Death. Dis. 5 (2014): e1496-   McClung, J. K. et al., Exp. Gerontol. 30 (1995): 99-124-   McDonald, J. M. et al., Mol. Cancer 4 (2005): 35-   Mechtcheriakova, D. et al., Cell Signal. 19 (2007): 748-760-   Mehta, A. et al., Breast 23 (2014): 2-9-   Mehta, J. et al., PLoS. One. 10 (2015): e0120622-   Meier, C. et al., J Pathol. 234 (2014): 351-364-   Meijer, D. et al., Breast Cancer Res Treat. 113 (2009): 253-260-   Meissner, M. et al., Clin Cancer Res 11 (2005): 2552-2560-   Men, W. et al., Cancer Genomics Proteomics. 12 (2015): 1-8-   Meng, F. et al., Int J Oncol 43 (2013): 495-502-   Meng, J. et al., Acta Biochim. Biophys. Sin. (Shanghai) 42 (2010):    52-57-   Mertens-Walker, I. et al., BMC. Cancer 15 (2015): 164-   Messai, Y. et al., Cancer Res 74 (2014): 6820-6832-   Metwally, N. S. et al., Cancer Cell Int. 11 (2011): 8-   Meziere, C. et al., J Immunol 159 (1997): 3230-3237-   Michel, S. et al., Int. J Cancer 127 (2010): 889-898-   Midorikawa, Y. et al., Jpn. J Cancer Res 93 (2002): 636-643-   Mikami, T. et al., Oral Oncol 47 (2011): 497-503-   Mikami, T. et al., Virchows Arch. 466 (2015): 559-569-   Milanovich, S. et al., Exp. Hematol. 43 (2015): 53-64-   Miller, R. K. et al., J Am. Soc. Nephrol. 22 (2011): 1654-1664-   Milne, R. L. et al., Hum. Mol. Genet. 23 (2014): 6096-6111-   Min, K. W. et al., Int. J Gynecol. Pathol. 32 (2013): 3-14-   Mino, K. et al., Biosci. Biotechnol. Biochem. 78 (2014): 1010-1017-   Mirmalek-Sani, S. H. et al., J Cell Mol. Med. 13 (2009): 3541-3555-   Mishra, L. et al., Cancer Biol Ther. 4 (2005a): 694-699-   Mishra, S. et al., FEBS J 277 (2010): 3937-3946-   Mishra, S. et al., Trends Mol. Med. 11 (2005b): 192-197-   Mitchell, R. J. et al., Hum. Hered. 38 (1988): 144-150-   Mitra, R. et al., Clin Cancer Res 17 (2011): 2934-2946-   Mitsuhashi, K. et al., Int. J Hematol. 100 (2014): 88-95-   Mittal, R. D. et al., Indian J Cancer 41 (2004): 115-119-   Miwa, H. et al., Leukemia 6 (1992): 405-409-   Miwa, T. et al., Cancer Med. 4 (2015): 1091-1100-   Miyaji, K. et al., J Viral Hepat. 10 (2003): 241-248-   Miyoshi, Y. et al., Med. Mol. Morphol. 43 (2010): 193-196-   Mo, L. et al., Anticancer Res 30 (2010): 3413-3420-   Mohamed, F. E. et al., Liver Int. 35 (2015): 1063-1076-   Mohelnikova-Duchonova, B. et al., Cancer Chemother. Pharmacol. 72    (2013a): 669-682-   Mohelnikova-Duchonova, B. et al., Pancreas 42 (2013b): 707-716-   Moldovan, G. L. et al., Mol. Cell Biol 30 (2010): 1088-1096-   Molinolo, A. A. et al., Clin Cancer Res 13 (2007): 4964-4973-   Moniz, L. S. et al., Mol. Cell Biol 31 (2011): 30-42-   Monji, M. et al., Clin Cancer Res 10 (2004): 6047-6057-   Morgan, R. A. et al., Science 314 (2006): 126-129-   Mori, M. et al., Transplantation 64 (1997): 1017-1027-   Mori, Y. et al., Endocr. Relat Cancer 18 (2011): 465-478-   Moritake, H. et al., Am. J Hematol. 86 (2011): 75-78-   Moriya, Y. et al., J Hum. Genet. 57 (2012): 38-45-   Mortara, L. et al., Clin Cancer Res. 12 (2006): 3435-3443-   Moss, S. F. et al., Gut 45 (1999): 723-729-   Mossink, M. H. et al., Oncogene 22 (2003): 7458-7467-   Mostafa, W. Z. et al., J Cutan. Pathol. 37 (2010): 68-74-   Motaghed, M. et al., Int. J Mol. Med. 33 (2014): 8-16-   Mouradov, D. et al., Cancer Res 74 (2014): 3238-3247-   Mueller, L. N. et al., J Proteome. Res 7 (2008): 51-61-   Mueller, L. N. et al., Proteomics. 7 (2007): 3470-3480-   Muir, K. et al., Cancer Res 73 (2013): 4722-4731-   Mulligan, A. M. et al., Breast Cancer Res 13 (2011): R110-   Mumberg, D. et al., Proc. Natl. Acad. Sci. U.S.A 96 (1999):    8633-8638-   Munoz, I. M. et al., Mol. Cell 35 (2009): 116-127-   Murphy, N. C. et al., Int. J Cancer 126 (2010): 1445-1453-   Murray, G. I. et al., Histopathology 57 (2010): 202-211-   Murrin, L. C. et al., J Neuroimmune. Pharmacol. 2 (2007): 290-295-   Murugan, A. K. et al., Oncol Lett. 6 (2013): 437-441-   Muto, Y. et al., Cell Cycle 7 (2008): 2738-2748-   Mydlikova, Z. et al., Neoplasma 57 (2010): 287-290-   Naba, A. et al., Elife. 3 (2014): e01308-   Nadal-Serrano, M. et al., J Cell Biochem. 113 (2012): 3178-3185-   Nagai, M. et al., Cancer Res 51 (1991): 3886-3890-   Nagai, M. A. et al., Int. J Oncol 37 (2010): 41-49-   Nagakura, S. et al., Blood 100 (2002): 1031-1037-   Nagamachi, A. et al., Cancer Cell 24 (2013): 305-317-   Nagashio, R. et al., Sci. Rep. 5 (2015): 8649-   Nagata, M. et al., BMC. Cancer 13 (2013): 410-   Nagendra, D. C. et al., Mol. Carcinog 51 (2012): 826-831-   Nagi, C. et al., Breast Cancer Res Treat. 94 (2005): 225-235-   Nagpal, J. K. et al., Mod. Pathol. 21 (2008): 979-991-   Nakagawa, Y. et al., Br. J Cancer 80 (1999): 914-917-   Nakaya, H. I. et al., Biochem. Biophys. Res Commun. 364 (2007):    918-923-   Nakayama, K. et al., Cancer Res 67 (2007): 8058-8064-   Nallar, S. C. et al., PLoS. One. 6 (2011): e24082-   Nam, S. H. et al., Oncotarget. 6 (2015): 21655-21674-   Nam, S. W. et al., Int. J Oncol 45 (2014): 1450-1456-   Nam-Cha, S. H. et al., Mod. Pathol. 22 (2009): 1006-1015-   Nantajit, D. et al., PLoS. One. 5 (2010): e12341-   Narita, T. et al., Mol Cell Biol. 23 (2003): 1863-1873-   Navarro, A. et al., J Clin Endocrinol. Metab 99 (2014): E2437-E2445-   Naylor, D. J. et al., J Biol Chem 273 (1998): 21169-21177-   Near, R. I. et al., J Cell Physiol 212 (2007): 655-665-   Nebral, K. et al., Leukemia 23 (2009): 134-143-   Neidert, M. C. et al., J Neurooncol. 111 (2013): 285-294-   Nelson, C. R. et al., J Cell Biol 211 (2015): 503-516-   Nelson, M. A. et al., Cancer Genet. Cytogenet. 108 (1999): 91-99-   Neumann, M. et al., Blood 121 (2013): 4749-4752-   Neveling, K. et al., Cytogenet. Genome Res 118 (2007): 166-176-   Ng, Y. et al., J Biol Chem 279 (2004): 34156-34164-   Ngeow, J. et al., Cancer Discov. 4 (2014): 762-763-   Nguyen, T. B. et al., J Biol Chem 277 (2002): 41960-41969-   Ni, I. B. et al., Hematol. Rep. 4 (2012): e19-   Ni, Y. H. et al., Histopathology (2015)-   Ni, Z. et al., J Urol. 167 (2002): 1859-1862-   Niavarani, A. et al., Ann. Hematol. (2015)-   Niimi, R. et al., BMC. Cancer 13 (2013): 309-   Nikonova, A. S. et al., Cell Mol. Life Sci. 70 (2013): 661-687-   Nikpour, P. et al., Med. Oncol 31 (2014): 955-   Nilsson, R. et al., Nat Commun. 5 (2014): 3128-   Nishi, T. et al., Pathol. Int. 62 (2012): 802-810-   Nishikata, M. et al., Mol. Carcinog 46 (2007): 208-214-   Niu, N. et al., Genome Res 20 (2010): 1482-1492-   Niu, N. et al., BMC. Cancer 12 (2012): 422-   Nobori, T. et al., Cancer Res 51 (1991): 3193-3197-   Nobori, T. et al., Cancer Res 53 (1993): 1098-1101-   Noll, J. E. et al., Neoplasia. 16 (2014): 572-585-   Nooter, K. et al., Br. J Cancer 76 (1997): 486-493-   Nord, H. et al., Neuro. Oncol 11 (2009): 803-818-   Norris, M. D. et al., N. Engl. J Med. 334 (1996): 231-238-   Noske, A. et al., Exp. Mol. Pathol. 98 (2015): 47-54-   Novikov, L. et al., Mol. Cell Biol 31 (2011): 4244-4255-   Nowarski, R. et al., Blood 120 (2012): 366-375-   Nymoen, D. A. et al., Gynecol. Oncol 139 (2015): 30-39-   O'Connor, K. W. et al., Cancer Res 73 (2013): 2529-2539-   O'Gorman, D. B. et al., Endocrinology 143 (2002): 4287-4294-   O'Malley, S. et al., Int. J Cancer 125 (2009): 1805-1813-   O'Reilly, J. A. et al., PLoS. One. 10 (2015): e0123469-   Oberg, E. A. et al., J Biol Chem 287 (2012): 43378-43389-   Obuchowska, I. et al., Klin. Oczna 101 (1999): 167-168-   Odvody, J. et al., Oncogene 29 (2010): 3287-3296-   Oehler, V. G. et al., Blood 114 (2009): 3292-3298-   Ogawa, C. et al., J Biol Chem 278 (2003): 1268-1272-   Ogawa, R. et al., Dis. Esophagus. 21 (2008): 288-297-   Oguri, T. et al., Mol. Cancer Ther. 7 (2008): 1150-1155-   Ohba, K. et al., J Urol. 174 (2005): 461-465-   Ohnishi, K. et al., Cancer Sci. 104 (2013): 1237-1244-   Ohshima, K. et al., Mol Biol. Evol. 27 (2010): 2522-2533-   Oishi, Y. et al., Tumour. Biol 33 (2012): 383-393-   Okada, M. et al., Proc. Natl. Acad. Sci. U.S.A 105 (2008): 8649-8654-   Okada, S. et al., J Oral Pathol. Med. 44 (2015): 115-125-   Okosun, J. et al., Nat Genet. 48 (2016): 183-188-   Olayioye, M. A. et al., J Biol Chem 280 (2005): 27436-27442-   Oleksowicz, L. et al., Cancer J Sci. Am. 4 (1998): 247-253-   Olesen, U. H. et al., APMIS 119 (2011): 296-303-   Olkhanud, P. B. et al., Cancer Res 69 (2009): 5996-6004-   Olsson, L. et al., Leukemia 28 (2014): 302-310-   Olsson, M. et al., Prostate 67 (2007): 1439-1446-   Ooe, A. et al., Breast Cancer Res Treat. 101 (2007): 305-315-   Orchel, J. et al., Int. J Gynecol. Cancer 22 (2012): 937-944-   Ostrow, K. L. et al., Clin Cancer Res 16 (2010): 3463-3472-   Ota, T. et al., Cancer Res 62 (2002): 5168-5177-   Ottaviani, S. et al., Cancer Immunol. Immunother. 55 (2006): 867-872-   Ou, C. Y. et al., J Biol Chem 284 (2009): 20629-20637-   Ozaki, Y. et al., Oncol Rep. 12 (2004): 1071-1077-   Ozawa, H. et al., Ann. Surg. Oncol 17 (2010): 2341-2348-   Ozbas-Gerceker, F. et al., Asian Pac. J Cancer Prev. 14 (2013):    5213-5217-   Ozgur, S. et al., RNA. Biol 10 (2013): 528-539-   Palma, M. et al., BMC. Clin Pathol. 12 (2012): 2-   Pan, B. et al., Mol. Biol Rep. 40 (2013): 27-33-   Pan, W. A. et al., RNA. Biol 12 (2015): 255-267-   Pandey, R. N. et al., Oncogene 29 (2010): 3715-3722-   Pankratz, V. S. et al., J Thorac. Oncol 6 (2011): 1488-1495-   Pannu, V. et al., Oncotarget. 6 (2015): 6076-6091-   Papadakis, M. et al., Fam. Cancer 14 (2015): 599-602-   Papp, B. et al., Biomolecules. 2 (2012): 165-186-   Parihar, A. et al., Life Sci. 82 (2008a): 1077-1082-   Parihar, M. S. et al., Biochim. Biophys. Acta 1780 (2008b): 921-926-   Parikh, R. A. et al., Genes Chromosomes. Cancer 53 (2014): 25-37-   Park, E. et al., Mol. Cell 50 (2013): 908-918-   Park, H. J. et al., J Proteome. Res 7 (2008): 1138-1150-   Park, S. H. et al., Clin Cancer Res. 13 (2007): 858-867-   Park, S. J. et al., Oncogene 35 (2016): 1292-1301-   Park, Y. et al., Oncogene 34 (2015): 5037-5045-   Park, Y. M. et al., Gene 551 (2014): 236-242-   Patil, A. A. et al., Oncotarget. 5 (2014): 6414-6424-   Patrick, A. N. et al., Nat Struct. Mol. Biol 20 (2013): 447-453-   Patrikainen, L. et al., Eur. J Clin Invest 37 (2007): 126-133-   Paulo, P. et al., Neoplasia. 14 (2012): 600-611-   Pavelec, D. M. et al., Genetics 183 (2009): 1283-1295-   Pawar, H. et al., Cancer Biol Ther. 12 (2011): 510-522-   Pawar, S. et al., J Ovarian. Res 7 (2014): 53-   Peddaboina, C. et al., BMC. Cancer 12 (2012): 541-   Peeters, M. C. et al., Cell Signal. 27 (2015): 2579-2588-   Peltonen, K. et al., Cancer Cell 25 (2014): 77-90-   Pelttari, L. M. et al., Fam. Cancer (2015)-   Pender-Cudlip, M. C. et al., Cancer Sci. 104 (2013): 760-764-   Peng, D. F. et al., Gut 58 (2009): 5-15-   Peng, H. X. et al., Biomed. Res Int. 2015 (2015a): 326981-   Peng, J. et al., Sichuan. Da. Xue. Xue. Bao. Yi. Xue. Ban. 46    (2015b): 413-416-   Peng, Y. et al., Cancer Res 75 (2015c): 378-386-   Perdigao, P. F. et al., Genes Chromosomes. Cancer 44 (2005): 204-211-   Pereira, J. S. et al., Endocrine. 49 (2015): 204-214-   Pereira, P. M. et al., Org. Biomol. Chem. 12 (2014): 1804-1811-   Perez, A. et al., Cancers (Basel) 6 (2014): 179-192-   Perez-Tomas, R., Curr. Med. Chem 13 (2006): 1859-1876-   Perrais, M. et al., J Biol Chem 276 (2001): 15386-15396-   Perrotti, D. et al., Lancet Oncol 14 (2013): e229-e238-   Personnic, N. et al., FEBS J 281 (2014): 2977-2989-   Perugorria, M. J. et al., Cancer Res 69 (2009): 1358-1367-   Pestov, D. G. et al., Mol. Cell Biol 21 (2001): 4246-4255-   Peters, D. G. et al., Cancer Epidemiol. Biomarkers Prev. 14 (2005):    1717-1723-   Peyrard, M. et al., Hum. Mol. Genet. 3 (1994): 1393-1399-   Peyre, M. et al., PLoS. One. 5 (2010): e12932-   Phipps-Yonas, H. et al., Front Immunol. 4 (2013): 425-   Phongpradist, R. et al., Curr. Pharm. Des 16 (2010): 2321-2330-   Piccolo, S. et al., Cancer Res 73 (2013): 4978-4981-   Piepoli, A. et al., Exp. Biol Med. (Maywood.) 237 (2012): 1123-1128-   Pils, D. et al., BMC. Cancer 13 (2013): 178-   Pinheiro, J. et al., nlme: Linear and Nonlinear Mixed Effects Models    (http://CRAN.R-project.org/packe=nlme) (2015)-   Pio, R. et al., Cancer Res 64 (2004): 4171-4179-   Pissimissis, N. et al., Anticancer Res 29 (2009): 371-377-   Pizzatti, L. et al., Biochim. Biophys. Acta 1764 (2006): 929-942-   Placke, T. et al., Blood 124 (2014): 13-23-   Pleasance, E. D. et al., Nature 463 (2010): 184-190-   Plebanski, M. et al., Eur. J Immunol 25 (1995): 1783-1787-   Pohl, A. et al., Pharmacogenomics. J 11 (2011): 93-99-   Poligone, B. et al., J Invest Dermatol. 135 (2015): 869-876-   Polisetty, R. V. et al., J Proteomics. 74 (2011): 1918-1925-   Pongor, L. et al., Genome Med. 7 (2015): 104-   Poomsawat, S. et al., J Oral Pathol. Med. 39 (2010): 793-799-   Poortinga, G. et al., Nucleic Acids Res 39 (2011): 3267-3281-   Popov, N. et al., Nat Cell Biol 9 (2007): 765-774-   Porkka, K. P. et al., Genes Chromosomes. Cancer 39 (2004): 1-10-   Porta, C. et al., Virology 202 (1994): 949-955-   Possuelo, L. G. et al., Rev Bras. Ginecol. Obstet. 35 (2013):    569-574-   Pozo, K. et al., Cancer Cell 24 (2013): 499-511-   Pradhan, M. P. et al., BMC. Syst. Biol 7 (2013): 141-   Prasad, M. L. et al., Head Neck 26 (2004): 1053-1057-   Prasad, N. K. et al., Carcinogenesis 29 (2008a): 25-34-   Prasad, N. K. et al., Tumour. Biol 29 (2008b): 330-341-   Prunier, C. et al., Cell Rep. (2015)-   Pu, H. et al., World J Surg. Oncol 13 (2015): 323-   Puig-Butille, J. A. et al., Oncotarget. 5 (2014): 1439-1451-   Puls, F. et al., Am. J Surg. Pathol. 38 (2014): 1307-1318-   Pulukuri, S. M. et al., Mol. Cancer Res 7 (2009): 1285-1293-   Pulvino, M. et al., Blood 120 (2012): 1668-1677-   Purrington, K. S. et al., Carcinogenesis 35 (2014): 1012-1019-   Qi, J. et al., Gut (2015)-   Qi, L. et al., Cancer Res 74 (2014): 1301-1306-   Qi, Y. et al., Proteomics. 5 (2005): 2960-2971-   Qian, Y. et al., Mol. Cancer 13 (2014): 176-   Qian, Z. et al., J Exp. Clin Cancer Res 29 (2010): 111-   Qin, Y. et al., Chin Med. J (Engl.) 127 (2014): 1666-1671-   Quan, J. J. et al., Tumour. Biol 36 (2015a): 8617-8624-   Quan, Y. et al., J Cancer 6 (2015b): 342-350-   Quayle, S. N. et al., Neuro Oncol 14 (2012): 1325-1331-   Quek, H. H. et al., DNA Cell Biol. 16 (1997): 275-280-   Quidville, V. et al., Cancer Res 73 (2013): 2247-2258-   Rahman, M. et al., Anticancer Res 33 (2013): 113-118-   Raja, S. B. et al., J Cell Sci. 125 (2012): 703-713-   Rajalingam, K. et al., Cell Cycle 4 (2005): 1503-1505-   Rajasagi, M. et al., Blood 124 (2014): 453-462-   Rajkumar, T. et al., BMC. Cancer 11 (2011): 80-   Ramachandran, C., Curr. Pharm. Biotechnol. 8 (2007): 99-104-   Rammensee, H. G. et al., Immunogenetics 50 (1999): 213-219-   Ran, Q. et al., PLoS. One. 9 (2014): e85328-   Rangel, L. B. et al., Oncogene 22 (2003): 7225-7232-   Rao, C. V. et al., Carcinogenesis 30 (2009): 1469-1474-   Rao, F. et al., Proc. Natl. Acad. Sci. U.S.A 112 (2015): 1773-1778-   Rappa, G. et al., Mol. Cancer Res 12 (2014): 1840-1850-   Rasinpera, H. et al., Gut 54 (2005): 643-647-   Rastetter, R. H. et al., BMC. Cancer 15 (2015): 638-   Rausch, M. P. et al., Mol. Immunol. 68 (2015): 124-128-   Rauscher, G. H. et al., BMC. Cancer 15 (2015): 816-   Rawluszko-Wieczorek, A. A. et al., J Cancer Res Clin Oncol 141    (2015): 1379-1392-   RefSeq, The NCBI handbook [Internet], Chapter 18, (2002),    www.ncbi.nlm.nih.gov/books/NBK21091/-   Rekhi, B. et al., Indian J Med. Res 136 (2012): 766-775-   Remmelink, M. et al., Int. J Oncol 26 (2005): 247-258-   Ren, G. et al., OMICS. 18 (2014): 615-624-   Ren, S. et al., Cell Res 22 (2012): 806-821-   Resende, C. et al., Helicobacter. 15 Suppl 1 (2010): 34-39-   Restifo, N. P. et al., J Exp. Med. 177 (1993): 265-272-   Reuschenbach, M. et al., Fam. Cancer 9 (2010): 173-179-   Rey, O. et al., Oncogene 18 (1999): 827-831-   Ribeiro, J. R. et al., Front Oncol 4 (2014): 45-   Rieger-Christ, K. M. et al., Hum. Pathol. 32 (2001): 18-23-   Ries, J. et al., Int. J Oncol 26 (2005): 817-824-   Rimkus, C. et al., Clin Gastroenterol. Hepatol. 6 (2008): 53-61-   Rini, B. I. et al., Cancer 107 (2006): 67-74-   Risch, H. A. et al., J Natl. Cancer Inst. 98 (2006): 1694-1706-   Ritterson, Lew C. et al., Nat Rev Urol. 12 (2015): 383-391-   Roberts, N. J. et al., Cancer Discov 2 (2012): 41-46-   Robin, T. P. et al., Mol. Cancer Res 10 (2012): 1098-1108-   Robles, L. D. et al., J Biol Chem 277 (2002): 25431-25438-   Rock, K. L. et al., Science 249 (1990): 918-921-   Rocken, C., Pathologe 34 (2013): 403-412-   Rodins, K. et al., Clin Cancer Res 8 (2002): 1075-1081-   Rodriguez-Paredes, M. et al., Oncogene 33 (2014): 2807-2813-   Rohrbeck, A. et al., PLoS. One. 4 (2009): e7315-   Rohrmoser, M. et al., Mol. Cell Biol 27 (2007): 3682-3694-   Roll, J. D. et al., Mol. Cancer 7 (2008): 15-   Romero, O. A. et al., Cancer Discov 4 (2014): 292-303-   Rondeau, S. et al., Br. J Cancer 112 (2015): 1059-1066-   Rosado, I. V. et al., RNA. 10 (2004): 1073-1083-   Ross, H. M. et al., Mod. Pathol. 24 (2011): 390-395-   Rothe, M. et al., Am. J Pathol. 157 (2000): 1597-1604-   Rudland, P. S. et al., Am. J Pathol. 176 (2010): 2935-2947-   Ruebel, K. H. et al., Endocrine. 29 (2006): 435-444-   Rumiato, E. et al., Cancer Chemother. Pharmacol. 72 (2013): 483-488-   Ruminy, P. et al., Leukemia 25 (2011): 681-688-   Russell, R. et al., Nat Commun. 6 (2015): 7677-   Ryu, B. et al., PLoS. One. 2 (2007): e594-   Ryu, H. S. et al., Thyroid 24 (2014): 1232-1240-   Ryu, S. J. et al., Expert. Opin. Ther. Targets. 13 (2009): 479-484-   S3-Leitlinie maligne Ovarialtumore, 032-0350L, (2013)-   Saddoughi, S. A. et al., Adv. Cancer Res. 117 (2013): 37-58-   Saeki, N. et al., Genes Chromosomes. Cancer 48 (2009): 261-271-   Saelee, P. et al., Asian Pac. J Cancer Prev. 10 (2009): 501-506-   Safadi, R. A. et al., Oral Surg. Oral Med. Oral Pathol. Oral Radiol.    121 (2016): 402-411-   Safarinejad, M. R. et al., Urol. Oncol 31 (2013): 1193-1203-   Sahab, Z. J. et al., J Cancer 1 (2010): 14-22-   Saiki, R. K. et al., Science 239 (1988): 487-491-   Saito, Y. et al., J Cancer Res Clin Oncol 139 (2013): 585-594-   Saito, Y. et al., Cancer Immunol. Res 3 (2015): 1356-1363-   Sajadian, S. O. et al., Clin Epigenetics. 7 (2015): 98-   Sakai, S. et al., Clin Chim. Acta 413 (2012): 1542-1548-   Sakamoto, S. et al., Cancer Res 70 (2010): 1885-1895-   Sakurikar, N. et al., J Biol Chem 287 (2012): 39193-39204-   Salon, C. et al., J Pathol. 213 (2007): 303-310-   Saloura, V. et al., Mol. Cancer Res 13 (2015): 293-304-   Samimi, G. et al., Cancer Epidemiol. Biomarkers Prev. 21 (2012):    273-279-   Sand, M. et al., Cell Tissue Res 350 (2012): 119-126-   Sang, Y. et al., Oncotarget. (2015)-   Sankar, S. et al., Mol. Cell Biol 33 (2013): 4448-4460-   Sankaran, D. et al., J Biol Chem 287 (2012): 5483-5491-   Santandreu, F. M. et al., Cell Physiol Biochem. 24 (2009): 379-390-   Santhekadur, P. K. et al., FEBS Open. Bio 4 (2014): 353-361-   Saraon, P. et al., Mol. Cell Proteomics. 12 (2013): 1589-1601-   Sarbia, M. et al., Am. J Clin Pathol. 128 (2007): 255-259-   Sarto, C. et al., Electrophoresis 18 (1997): 599-604-   Sastre-Serra, J. et al., Free Radic. Biol Med. 61 (2013): 11-17-   Sato, F. et al., Int. J Mol. Med. 30 (2012a): 495-501-   Sato, T. et al., PLoS. One. 8 (2013): e59444-   Sato, T. et al., J Cell Sci. 125 (2012b): 1544-1555-   Satoh, A. et al., Oncogene 23 (2004): 8876-8886-   Sattler, M. et al., Cancer Cell 1 (2002): 479-492-   Savoy, R. M. et al., Endocr. Relat Cancer 20 (2013): R341-R356-   Sawicka-Gutaj, N. et al., Tumour. Biol 36 (2015): 7859-7863-   Sayagues, J. M. et al., Med. Clin (Barc.) 128 (2007): 226-232-   Scagliotti, G. V. et al., Ann. Oncol 10 Suppl 5 (1999): S83-S86-   Scanlan, M. J. et al., Cancer Immun. 1 (2001): 4-   Scanlan, M. J. et al., Cancer Res 62 (2002): 4041-4047-   Schaner, M. E. et al., Mol. Biol Cell 14 (2003): 4376-4386-   Scharadin, T. M. et al., PLoS. One. 6 (2011): e23230-   Scheffer, G. L. et al., Curr. Opin. Oncol 12 (2000): 550-556-   Schiffmann, S. et al., Carcinogenesis 30 (2009): 745-752-   Schimanski, C. C. et al., Oncogene 24 (2005): 3100-3109-   Schleiermacher, G. et al., Oncogene 24 (2005): 3377-3384-   Schlumbrecht, M. P. et al., Mod. Pathol. 24 (2011): 453-462-   Schmidt, S. V. et al., Oncotarget. 6 (2015): 8635-8647-   Schoppmann, S. F. et al., Clin Cancer Res 19 (2013): 5329-5339-   Schraders, M. et al., Br. J Haematol. 143 (2008): 210-221-   Schramm, A. et al., Nat Genet. 47 (2015): 872-877-   Schrier, S. A. et al., Curr. Opin. Ophthalmol. 22 (2011): 325-331-   Schuetz, J. M. et al., Cancer Epidemiol. Biomarkers Prev. 21 (2012):    2272-2274-   Schulte, I. et al., BMC. Genomics 13 (2012): 719-   Scott, A. F. et al., Genes (Basel) 5 (2014): 366-384-   Scotto, L. et al., Genes Chromosomes. Cancer 47 (2008): 755-765-   Sears, D. et al., Cell Death. Dis. 1 (2010): e93-   Sedoris, K. C. et al., BMC. Cancer 10 (2010): 157-   Seeger, F. H. et al., Immunogenetics 49 (1999): 571-576-   Seeling, J. M. et al., Science 283 (1999): 2089-2091-   Seetoo, D. Q. et al., J Surg. Oncol 82 (2003): 184-193-   Seidel, C. et al., Mol. Carcinog 46 (2007): 865-871-   Seidl, C. et al., Invest New Drugs 28 (2010): 49-60-   Sekine, I. et al., Jpn. J Clin Oncol 37 (2007): 329-336-   Selamat, S. A. et al., PLoS. One. 6 (2011): e21443-   Seliger, B., Methods Mol. Biol 1102 (2014): 367-380-   Seliger, B. et al., Proteomics. 5 (2005): 2631-2640-   Seo, S. W. et al., J Orthop. Res 29 (2011): 1131-1136-   Seol, H. S. et al., Cancer Lett. 353 (2014): 232-241-   Seriramalu, R. et al., Electrophoresis 31 (2010): 2388-2395-   Servais, E. L. et al., Clin Cancer Res 18 (2012): 2478-2489-   Seshagiri, S. et al., Nature 488 (2012): 660-664-   Shackelford, R. E. et al., Int. J Clin Exp. Pathol. 3 (2010):    522-527-   Shadeo, A. et al., BMC. Genomics 9 (2008): 64-   Shah, S. P. et al., Nature 461 (2009): 809-813-   Shah, T. M. et al., Oral Oncol 49 (2013): 604-610-   Shames, D. S. et al., Clin Cancer Res 19 (2013): 6912-6923-   Shan, T. et al., Oncol Rep. 32 (2014): 1564-1570-   Shang, B. et al., Cell Death. Dis. 5 (2014): e1285-   Shao, J. et al., PLoS. One. 9 (2014): e97085-   Sharma, A. et al., Tumour. Biol 34 (2013): 3249-3257-   Shaughnessy, J. D., Jr. et al., Blood 118 (2011): 3512-3524-   Shaw, E. J. et al., Cell Oncol (Dordr.) 34 (2011): 355-367-   Shen, C. et al., Cancer Res 73 (2013): 3393-3401-   Shen, Y. et al., Oncotarget. 6 (2015a): 20396-20403-   Shen, Y. et al., Cancer Cell Microenviron. 2 (2015b)-   Sheng, S. H. et al., Clin Transl. Oncol 16 (2014): 153-157-   Sherman, F. et al., Laboratory Course Manual for Methods in Yeast    Genetics (1986)-   Shi, D. et al., Biochem. Biophys. Res Commun. 450 (2014a): 1241-1246-   Shi, H. et al., World J Surg. Oncol 12 (2014b): 188-   Shi, J. et al., Oncogene 25 (2006): 4923-4936-   Shi, J. et al., Am. J Cancer Res 2 (2012): 116-129-   Shi, J. L. et al., Oncotarget. 6 (2015): 5299-5309-   Shields, B. J. et al., Mol. Cell Biol 33 (2013): 557-570-   Shih, IeM et al., Am. J Pathol. 178 (2011): 1442-1447-   Shin, E. M. et al., J Clin Invest 124 (2014): 3807-3824-   Shiraishi, T. et al., J Transl. Med. 9 (2011): 153-   Shishkin, S. S. et al., Biochemistry (Mosc.) 78 (2013): 1415-1430-   Shruthi, D. K. et al., J Oral Maxillofac. Pathol. 18 (2014): 365-371-   Shtutman, M. et al., Proc. Natl. Acad. Sci. U.S.A 108 (2011):    12449-12454-   Shu, G. S. et al., Cancer Biomark. 11 (2012): 107-114-   Shu, J. et al., Cancer Res. 66 (2006): 5077-5084-   Sidhar, S. K. et al., Hum. Mol. Genet. 5 (1996): 1333-1338-   Siligan, C. et al., Oncogene 24 (2005): 2512-2524-   Silva, J. M. et al., Cell 137 (2009): 1047-1061-   Silveira, S. M. et al., PLoS. One. 8 (2013): e67643-   Simaga, S. et al., Eur. J Cancer 34 (1998): 399-405-   Simaga, S. et al., Gynecol. Oncol 91 (2003): 194-200-   Simonova, O. A. et al., Mol. Biol (Mosk) 49 (2015): 667-677-   Simons, A. L. et al., Lab Invest 93 (2013): 711-719-   Singh, G., Pharmaceuticals. (Basel) 7 (2014): 192-206-   Singh, H. et al., Am. J Obstet. Gynecol. 198 (2008): 303-306-   Singh, P. K. et al., Immunobiology 220 (2015): 103-108-   Singh, R. et al., FEBS J 281 (2014): 1629-1641-   Singh-Jasuja, H. et al., Cancer Immunol. Immunother. 53 (2004):    187-195-   Sinha, S. et al., Mol. Oncol 5 (2011): 454-464-   Skandalis, S. S. et al., Matrix Biol 35 (2014): 182-193-   Slattery, M. L. et al., Carcinogenesis 31 (2010): 1604-1611-   Slattery, M. L. et al., Mol. Carcinog 52 (2013): 155-166-   Slipicevic, A. et al., BMC. Cancer 8 (2008): 276-   Smaaland, R. et al., Breast Cancer Res Treat. 9 (1987): 53-59-   Small, E. J. et al., J Clin Oncol. 24 (2006): 3089-3094-   Smetsers, S. et al., Fam. Cancer 11 (2012): 661-665-   Smith, B. et al., Cell Rep. 2 (2012): 580-590-   Smith, J. B. et al., Gynecol. Oncol 134 (2014): 181-189-   Sohr, S. et al., Cell Cycle 7 (2008): 3448-3460-   Soman, N. R. et al., Proc. Natl. Acad. Sci. U.S.A 88 (1991):    4892-4896-   Soman, N. R. et al., Proc. Natl. Acad. Sci. U.S.A 87 (1990): 738-742-   Song, B. et al., Mol. Cancer Ther. 12 (2013a): 58-68-   Song, J. et al., World J Gastroenterol. 19 (2013b): 4127-4136-   Song, L. J. et al., J Mol. Med. (Berl) 90 (2012): 707-718-   Song, N. et al., J Zhejiang. Univ Sci. B 14 (2013c): 451-459-   Song, T. et al., Oncol Lett. 9 (2015a): 2799-2804-   Song, X. et al., Monoclon. Antib. Immunodiagn. Immunother. 33    (2014a): 246-253-   Song, X. C. et al., Mol. Cell Proteomics. 7 (2008): 163-169-   Song, Y. et al., Nature 509 (2014b): 91-95-   Song, Y. et al., Int. J Clin Exp. Pathol. 8 (2015b): 11314-11322-   Song, Y. et al., Biochem. J 406 (2007): 427-436-   Sonora, C. et al., J Histochem. Cytochem. 54 (2006): 289-299-   Soupene, E. et al., J Lipid Res. 49 (2008): 1103-1112-   Sousa, S. F. et al., Endocr. Relat Cancer 22 (2015): 399-408-   Sowalsky, A. G. et al., Cancer Res 71 (2011): 758-767-   Sowalsky, A. G. et al., Mol. Cancer Res. 13 (2015): 98-106-   Sporn, J. C. et al., Am. J Pathol. 180 (2012): 2516-2526-   Spyropoulou, A. et al., Neuromolecular. Med. 16 (2014): 70-82-   Srinivasan, D. et al., Cancer Res 66 (2006): 5648-5655-   Srinivasan, D. et al., Oncogene 27 (2008): 1095-1105-   St-Denis, N. et al., Mol. Cell Proteomics. 14 (2015): 946-960-   Stacey, S. N. et al., Nat Commun. 6 (2015): 6825-   Stadler, W. M. et al., Cancer Res 54 (1994): 2060-2063-   Stangel, D. et al., J Surg. Res 197 (2015): 91-100-   Stary, S. et al., Genes Chromosomes. Cancer 52 (2013): 33-43-   Stawerski, P. et al., Pol. J Pathol. 61 (2010): 219-223-   Stefanska, B. et al., Clin Cancer Res 20 (2014): 3118-3132-   Steffen, J. S. et al., Virchows Arch. 461 (2012): 355-365-   Steinbach, D. et al., Clin Cancer Res 12 (2006): 4357-4363-   Steinestel, K. et al., Mol. Cancer 13 (2014): 145-   Steinestel, K. et al., Pathologe 34 Suppl 2 (2013): 189-194-   Steinmann, K. et al., Oncol Rep. 22 (2009): 1519-1526-   Stirewalt, D. L. et al., Genes Chromosomes. Cancer 47 (2008): 8-20-   Stirpe, F. et al., Am. J Gastroenterol. 97 (2002): 2079-2085-   Stoiber, D. et al., J Clin Invest 114 (2004): 1650-1658-   Stone, B. et al., Gene 267 (2001): 173-182-   Stransky, N. et al., Nat Commun. 5 (2014): 4846-   Strock, C. J. et al., Cancer Res 66 (2006): 7509-7515-   Strojnik, T. et al., Anticancer Res 26 (2006): 2887-2900-   Strojnik, T. et al., Anticancer Res 29 (2009): 3269-3279-   Stubbs, A. P. et al., Am. J Pathol. 154 (1999): 1335-1343-   Sturm, M. et al., BMC. Bioinformatics. 9 (2008): 163-   Su, M. T. et al., Gynecol. Oncol 103 (2006): 357-360-   Su, Y. F. et al., J Biomed. Sci. 21 (2014): 67-   Subramanian, M. et al., J Clin Endocrinol. Metab 94 (2009):    1467-1471-   Suchy, J. et al., BMC. Cancer 8 (2008): 112-   Sud, N. et al., Int. J Cancer 112 (2004): 905-907-   Sudo, H. et al., Genomics 95 (2010): 210-216-   Sueoka, S. et al., Ann. Surg. Oncol (2015)-   Sugano, G. et al., Oncogene 30 (2011): 642-653-   Sugimoto, K. J. et al., Int. J Clin Exp. Pathol. 7 (2014): 8980-8987-   Sugimoto, T. et al., Genes Chromosomes. Cancer 48 (2009): 132-142-   Suh, J. H. et al., Mol. Endocrinol. 22 (2008): 33-46-   Sukocheva, O. A. et al., World J Gastroenterol. 21 (2015): 6146-6156-   Sullivan, G. F. et al., J Clin Invest 105 (2000): 1261-1267-   Sun, A. et al., Prostate (2015a)-   Sun, D. W. et al., Cancer Epidemiol. (2015b)-   Sun, H. et al., J BUON. 20 (2015c): 296-308-   Sun, J. Y. et al., Zhonghua Kou Qiang. Yi. Xue. Za Zhi. 39 (2004a):    114-117-   Sun, K. et al., Tumour. Biol 36 (2015d): 1549-1559-   Sun, N. K. et al., Oncotarget. 6 (2015e): 27065-27082-   Sun, Q. Y. et al., J Pathol. 235 (2015f): 559-570-   Sun, S. et al., Gene 584 (2016): 90-96-   Sun, S. et al., J Proteome. Res 9 (2010): 70-78-   Sun, W. et al., Cancer Lett. 212 (2004b): 83-93-   Sun, X. et al., Int. J Oncol 44 (2014a): 1678-1684-   Sun, Y. et al., Oncogene 34 (2015g): 2527-2537-   Sun, Y. et al., Carcinogenesis 35 (2014b): 1941-1950-   Sun, Y. et al., Eur. J Cancer Prev. 23 (2014c): 418-424-   Sun, Y. et al., Asian J Androl 16 (2014d): 319-324-   Sung, W. W. et al., BMC. Cancer 14 (2014): 951-   Surmann, E. M. et al., Cancer Immunol. Immunother. 64 (2015):    357-366-   Suzuki, H. et al., Lung Cancer 59 (2008): 24-31-   Svendsen, J. M. et al., Cell 138 (2009): 63-77-   Svojgr, K. et al., Immunol. Lett. 122 (2009): 185-192-   Svojgr, K. et al., Exp. Hematol. 40 (2012): 379-385-   Swanson, K. D. et al., Genes Chromosomes. Cancer 47 (2008): 253-259-   Swift, M. et al., N. Engl. J Med. 316 (1987): 1289-1294-   Symes, A. J. et al., PLoS. One. 8 (2013): e84295-   Szabo, P. M. et al., Virchows Arch. 455 (2009): 133-142-   Szaflarski, W. et al., Postepy Biochem. 57 (2011): 266-273-   Szczepanski, M. J. et al., Oral Oncol 49 (2013): 144-151-   Szczepanski, M. J. et al., Biomark. Med. 7 (2013): 575-578-   Szuhai, K. et al., Clin Cancer Res 15 (2009): 2259-2268-   Tagawa, H., Nihon Rinsho 72 (2014): 1052-1057-   Tahara, H. et al., Prostate Cancer Prostatic. Dis. 18 (2015): 56-62-   Tahara, K. et al., Cancer 85 (1999): 1234-1240-   Tahara, T. et al., Gastroenterology 146 (2014): 530-538-   Tai, C. J. et al., Int. J Biol Markers 27 (2012): e280-e284-   Tai, W. et al., Mol. Pharm. 10 (2013): 477-487-   Takahashi, K. et al., Int. J Oncol 28 (2006): 321-328-   Takahashi, Y. et al., Ann. Oncol 26 (2015): 935-942-   Takao, M. et al., Oncol Rep. 17 (2007): 1333-1339-   Takaoka, N. et al., BMC. Mol. Biol 12 (2011): 31-   Takashima, S. et al., Tumour. Biol. 35 (2014): 4257-4265-   Takata, A. et al., Hepatology 57 (2013a): 162-170-   Takata, K. et al., Nat Commun. 4 (2013b): 2338-   Takayanagi, S. et al., J Exp. Ther. Oncol 4 (2004): 239-246-   Takeda, S. et al., J Toxicol. Sci. 39 (2014): 711-716-   Takemoto, H. et al., Int. J Cancer 91 (2001): 783-788-   Takenokuchi, M. et al., Anticancer Res 35 (2015): 3307-3316-   Takeyama, K. et al., J Biol Chem 278 (2003): 21930-21937-   Talieri, M. et al., Thromb. Haemost. 91 (2004): 180-186-   Tamir, A. et al., J Ovarian. Res 7 (2014): 109-   Tan, J. A. et al., Mol. Cell Endocrinol. 382 (2014): 302-313-   Tan, P. et al., Biochem. Biophys. Res Commun. 419 (2012): 801-808-   Tan, X. et al., Int. J Cancer 123 (2008): 1080-1088-   Tanahashi, N. et al., Biochem. Biophys. Res Commun. 243 (1998):    229-232-   Tanaka, M. et al., Cancer Sci. 99 (2008a): 979-985-   Tanaka, Y. et al., J Hepatol. 49 (2008b): 746-757-   Tang, C. Y. et al., Clin Chem Lab Med. 52 (2014a): 1843-1850-   Tang, H. et al., Int. J Mol. Med. 32 (2013): 381-388-   Tang, N. et al., Sheng Li Xue. Bao. 62 (2010): 196-202-   Tang, S. et al., Xi. Bao. Yu Fen. Zi. Mian. Yi. Xue. Za Zhi. 30    (2014b): 411-413-   Taniuchi, K. et al., Cancer Res 65 (2005): 105-112-   Tanner, M. M. et al., Clin Cancer Res 1 (1995): 1455-1461-   Tano, K. et al., FEBS Lett. 584 (2010): 4575-4580-   Tao, F. et al., World J Gastroenterol. 20 (2014a): 9564-9569-   Tao, J. et al., Tumour. Biol 35 (2014b): 4389-4399-   Tao, T. et al., Cell Res 23 (2013): 620-634-   Taouji, S. et al., J Biol Chem 288 (2013): 17190-17201-   Tarcic, O. et al., Cell Rep. 14 (2016): 1462-1476-   Tatidis, L. et al., J Lipid Res 38 (1997): 2436-2445-   Tatsuka, M. et al., Cancer Res 58 (1998): 4811-4816-   Taube, E. T. et al., Gynecol. Oncol 140 (2016): 494-502-   Tedeschi, P. M. et al., Mol. Cancer Res (2015)-   Teh, M. T. et al., Cancer Res 62 (2002): 4773-4780-   Terada, T., Int. J Clin Exp. Pathol. 5 (2012): 596-600-   Teufel, R. et al., Cell Mol Life Sci. 62 (2005): 1755-1762-   Thakkar, A. D. et al., Biomark. Cancer 2 (2010): 1-15-   Thang, N. D. et al., Oncotarget. 6 (2015): 14290-14299-   Theiss, A. L. et al., Biochim. Biophys. Acta 1813 (2011): 1137-1143-   Thomas, A. et al., Cancer Med. 2 (2013): 836-848-   Thome, C. H. et al., Mol. Cell Proteomics. 11 (2012): 1898-1912-   Thompson, D. A. et al., Eur. J Biochem. 252 (1998): 169-177-   Thorell, K. et al., BMC. Med. Genomics 2 (2009): 53-   Tian, X. et al., Oncol Rep. 34 (2015): 707-714-   Tibaldi, L. et al., PLoS. One. 8 (2013): e72708-   Timofeeva, O. A. et al., Int. J Oncol 35 (2009): 751-760-   Tomiyama, L. et al., Oncogene 34 (2015): 1141-1149-   Tomonaga, M. et al., Int. J Oncol 40 (2012): 409-417-   Tong, W. G. et al., Epigenetics. 5 (2010): 499-508-   Toogeh, G. et al., Clin Lymphoma Myeloma. Leuk. 16 (2016): e21-e26-   Torres-Reyes, L. A. et al., Int. J Clin Exp. Pathol. 7 (2014):    7409-7418-   Tozbikian, G. et al., PLoS. One. 9 (2014): e114900-   Tran, E. et al., Science 344 (2014): 641-645-   Travis, R. C. et al., Int. J Cancer 132 (2013): 1901-1910-   Trehoux, S. et al., Biochem. Biophys. Res Commun. 456 (2015):    757-762-   Trifonov, V. et al., BMC. Syst. Biol 7 (2013): 25-   Tripodi, D. et al., BMC. Med. Genomics 2 (2009): 65-   Trotta, C. R. et al., Nature 441 (2006): 375-377-   Tsai, F. M. et al., Cell Signal. 18 (2006): 349-358-   Tsao, D. A. et al., DNA Cell Biol 29 (2010): 285-293-   Tsao, T. Y. et al., Mol. Cell Biochem. 327 (2009): 163-170-   Tsou, J. H. et al., J Pathol. 225 (2011): 243-254-   Tsujikawa, T. et al., Int. J Cancer 132 (2013): 2755-2766-   Tsukamoto, Y. et al., J Pathol. 216 (2008): 471-482-   Tsuruga, T. et al., Oncol Res 16 (2007): 431-435-   Tu, L. C. et al., Mol. Cell Proteomics. 6 (2007): 575-588-   Tucci, M. et al., Curr. Top. Med. Chem 9 (2009): 218-224-   Tummala, R. et al., Cancer Chemother. Pharmacol. 64 (2009):    1187-1194-   Tung, M. C. et al., Cancer Epidemiol. Biomarkers Prev. 18 (2009):    1570-1577-   Tung, P. Y. et al., Stem Cells 31 (2013): 2330-2342-   Turner, A. et al., PLoS. One. 8 (2013): e56817-   Turner, B. C. et al., Cancer Res 58 (1998): 5466-5472-   Turtoi, A. et al., J Proteome. Res 10 (2011): 4302-4313-   Twa, D. D. et al., J Pathol. 236 (2015): 136-141-   Uchikado, Y. et al., Int. J Oncol 29 (2006): 1337-1347-   Uchiyama, K. et al., J Cell Biol. 159 (2002): 855-866-   Uemura, M. et al., Cancer 97 (2003): 2474-2479-   Ulloa, F. et al., PLoS. One. 10 (2015): e0119707-   Unger, K. et al., Endocr. Relat Cancer 17 (2010): 87-98-   Urbanucci, A. et al., Oncogene 31 (2012): 2153-2163-   Uyama, H. et al., Clin Cancer Res 12 (2006): 6043-6048-   Vahedi, S. et al., Oncol Rep. 34 (2015): 43-50-   Vainio, P. et al., PLoS. One. 7 (2012): e39801-   Vairaktaris, E. et al., Anticancer Res 27 (2007): 4121-4125-   Vaites, L. P. et al., Mol. Cell Biol 31 (2011): 4513-4523-   Vakana, E. et al., PLoS. One. 8 (2013): e78780-   Valles, I. et al., PLoS. One. 7 (2012): e42086-   Valque, H. et al., PLoS. One. 7 (2012): e46699-   van de Rijn, M. et al., Am. J Pathol. 161 (2002): 1991-1996-   van den Heuvel-Eibrink M M et al., Int. J Clin Pharmacol. Ther. 38    (2000): 94-110-   van der Zwan, Y. G. et al., Eur. Urol. 67 (2015): 692-701-   van Dijk, J. R. et al., Biochem. J 459 (2014): 27-36-   Van Ginkel, P. R. et al., Biochim. Biophys. Acta 1448 (1998):    290-297-   van Vuurden, D. G. et al., Neuro. Oncol 16 (2014): 946-959-   van, Agthoven T. et al., J Clin Oncol 27 (2009): 542-549-   van, Dam S. et al., BMC. Genomics 13 (2012): 535-   Van, Seuningen, I et al., Biochem. J 348 Pt 3 (2000): 675-686-   Vanaja, D. K. et al., Clin Cancer Res 12 (2006): 1128-1136-   Vanderstraeten, A. et al., Cancer Immunol. Immunother. 63 (2014):    545-557-   Vanharanta, S. et al., Elife. 3 (2014)-   Vanneste, D. et al., Curr. Biol. 19 (2009): 1712-1717-   Vasca, V. et al., Oncol Lett. 8 (2014): 2501-2504-   Vater, I. et al., Leukemia 29 (2015): 677-685-   Vavougios, G. D. et al., Am. J Physiol Lung Cell Mol. Physiol 309    (2015): L677-L686-   Veigaard, C. et al., Cancer Genet. 204 (2011): 516-521-   Vekony, H. et al., Oral Oncol 45 (2009): 259-265-   Venere, M. et al., Sci. Transl. Med. 7 (2015): 304ra143-   Verheugd, P. et al., Nat Commun. 4 (2013): 1683-   Vermeulen, C. F. et al., Gynecol. Oncol 105 (2007): 593-599-   Vey, N. et al., Oncogene 23 (2004): 9381-9391-   Vincent, A. et al., Oncotarget. 5 (2014): 2575-2587-   Vincent-Chong, V. K. et al., Oral Dis. 18 (2012): 469-476-   Viswanathan, M. et al., Clin Cancer Res 9 (2003): 1057-1062-   Vitale, M. et al., Cancer Res 58 (1998): 737-742-   Vlaykova, T. et al., J BUON. 16 (2011): 265-273-   Vogetseder, A. et al., Int. J Cancer 133 (2013): 2362-2371-   Volkmer, J. P. et al., Proc. Natl. Acad. Sci. U.S.A 109 (2012):    2078-2083-   Vrabel, D. et al., Klin. Onkol. 27 (2014): 340-346-   Walker, F. et al., Biol Chem 395 (2014): 1075-1086-   Walsh, M. D. et al., Mod. Pathol. 26 (2013): 1642-1656-   Walter, S. et al., J Immunol 171 (2003): 4974-4978-   Walter, S. et al., Nat Med. 18 (2012): 1254-1261-   Wang, B. S. et al., Clin Sci. (Lond) 124 (2013a): 203-214-   Wang, B. S. et al., Cell Stress. Chaperones. 18 (2013b): 359-366-   Wang, C. et al., Mol. Cancer Res 5 (2007a): 1031-1039-   Wang, C. et al., Nucleic Acids Res 43 (2015a): 4893-4908-   Wang, C. et al., Clin Cancer Res 4 (1998): 567-576-   Wang, C. J. et al., Mol. Biol Rep. 40 (2013c): 6525-6531-   Wang, C. X. et al., Asian Pac. J Cancer Prev. 15 (2014a): 355-362-   Wang, D. et al., J Biol. Chem. 277 (2002): 36216-36222-   Wang, E. et al., Proc. Natl. Acad. Sci. U.S.A 110 (2013d): 3901-3906-   Wang, F. et al., Oncol Rep. 30 (2013e): 260-268-   Wang, G. et al., Biochem. J 446 (2012a): 415-425-   Wang, G. R. et al., Acta Pharmacol. Sin. 30 (2009a): 1436-1442-   Wang, H. et al., J Biol. Chem 289 (2014b): 4009-4017-   Wang, H. et al., J Biol Chem 289 (2014c): 23123-23131-   Wang, H. et al., Chin Med. J (Engl.) 116 (2003): 1074-1077-   Wang, H. et al., J Cancer Res Ther. 11 Suppl 1 (2015b): C74-C79-   Wang, J. et al., Oncotarget. 6 (2015c): 16527-16542-   Wang, J. et al., Asian Pac. J Cancer Prev. 14 (2013f): 2805-2809-   Wang, J. W. et al., Oncogene 23 (2004): 4089-4097-   Wang, K. et al., J Biol Chem 289 (2014d): 23928-23937-   Wang, L. et al., Acta Med. Okayama 65 (2011): 315-323-   Wang, L. et al., Int. J Cancer 124 (2009b): 1526-1534-   Wang, L. et al., Cancer Cell 25 (2014e): 21-36-   Wang, M. et al., Int. J Mol. Med. 33 (2014f): 1019-1026-   Wang, N. et al., Mol. Biol Rep. 39 (2012b): 10497-10504-   Wang, P. et al., Zhongguo Fei. Ai. Za Zhi. 12 (2009c): 875-878-   Wang, Q. et al., Cell 138 (2009d): 245-256-   Wang, Q. et al., Mol. Med. Rep. 12 (2015d): 475-481-   Wang, S. S. et al., PLoS. One. 5 (2010): e8667-   Wang, S. Y. et al., Oncotarget. 7 (2016a): 2878-2888-   Wang, T. et al., Clin Transl. Oncol 17 (2015e): 564-569-   Wang, V. W. et al., Head Neck 35 (2013g): 831-835-   Wang, W. W. et al., Int. J Clin Exp. Med. 8 (2015f): 3063-3071-   Wang, W. X. et al., Sichuan. Da. Xue. Xue. Bao. Yi. Xue. Ban. 40    (2009e): 857-860-   Wang, X. et al., Int. J Clin Exp. Med. 8 (2015g): 1780-1791-   Wang, X. et al., Hum. Pathol. 44 (2013h): 2020-2027-   Wang, X. et al., Am. J Cancer Res 5 (2015h): 2590-2604-   Wang, X. et al., J Biol Chem 290 (2015i): 3925-3935-   Wang, X. et al., Oncotarget. 7 (2016b): 8029-8042-   Wang, X. et al., Hum. Immunol. 75 (2014g): 1203-1209-   Wang, X. et al., Biochim. Biophys. Acta 1783 (2008): 1220-1228-   Wang, X. et al., Int. J Biol Markers 29 (2014h): e150-e159-   Wang, X. X. et al., Hepatobiliary. Pancreat. Dis. Int. 12 (2013i):    540-545-   Wang, X. X. et al., PLoS. One. 9 (2014i): e96501-   Wang, Y. et al., J Thorac. Dis. 7 (2015j): 672-679-   Wang, Y. et al., Oncogene 31 (2012c): 2512-2520-   Wang, Y. et al., J Biomed. Sci. 22 (2015k): 52-   Wang, Y. et al., Pathol. Oncol Res. 20 (2014): 611-618-   Wang, Y. F. et al., Tumour. Biol 34 (2013j): 1685-1689-   Wang, Z. et al., Cancer Res 67 (2007b): 8293-8300-   Warfel, N. A. et al., Cell Cycle 12 (2013): 3689-3701-   Waseem, A. et al., Oral Oncol 46 (2010): 536-542-   Watanabe, M. et al., Proteomics. Clin Appl. 2 (2008): 925-935-   Watanabe, T. et al., Clin Colorectal Cancer 10 (2011): 134-141-   Waters, M. G. et al., Nature 349 (1991): 248-251-   Watson, P. J. et al., Traffic. 5 (2004): 79-88-   Watts, C. A. et al., Chem Biol 20 (2013): 1399-1410-   Wazir, U. et al., Cancer Genomics Proteomics. 10 (2013): 69-73-   Wazir, U. et al., Oncol Rep. 33 (2015a): 1450-1458-   Wazir, U. et al., Oncol Rep. 33 (2015b): 2575-2582-   Weber, A. M. et al., Pharmacol. Ther (2014)-   Weeks, L. D. et al., Mol. Cancer Ther. 12 (2013): 2248-2260-   Wegiel, B. et al., J Natl. Cancer Inst. 100 (2008): 1022-1036-   Wei, P. et al., J Transl. Med. 11 (2013): 313-   Wei, X. et al., Nat Genet. 43 (2011): 442-446-   Wei, Y. P. et al., Xi. Bao. Yu Fen. Zi. Mian. Yi. Xue. Za Zhi. 28    (2012): 354-357-   Weidle, U. H. et al., Clin Exp. Metastasis 32 (2015): 623-635-   Weigert, O. et al., Cancer Discov 2 (2012): 47-55-   Wen, J. L. et al., PLoS. One. 10 (2015): e0115622-   Wenzel, J. et al., Int. J Cancer 123 (2008): 2605-2615-   Werner, S. et al., J Biol Chem 288 (2013): 22993-23008-   Weterman, M. A. et al., Cytogenet. Cell Genet. 92 (2001): 326-332-   Weterman, M. A. et al., Proc. Natl. Acad. Sci. U.S.A 93 (1996):    15294-15298-   Wharton, S. B. et al., Neuropathol. Appl. Neurobiol. 27 (2001):    305-313-   Wheler, J. J. et al., BMC. Cancer 15 (2015): 442-   Whitaker-Menezes, D. et al., Cell Cycle 10 (2011): 4047-4064-   White, C. D. et al., BMC. Gastroenterol. 10 (2010): 125-   Wijdeven, R. H. et al., Cancer Res 75 (2015): 4176-4187-   Wikman, H. et al., Genes Chromosomes. Cancer 42 (2005): 193-199-   Willcox, B. E. et al., Protein Sci. 8 (1999): 2418-2423-   Williams, K. A. et al., PLoS. Genet. 10 (2014): e1004809-   Wilson, I. M. et al., Oncogene 33 (2014): 4464-4473-   Wilting, S. M. et al., Genes Chromosomes. Cancer 47 (2008): 890-905-   Wirtenberger, M. et al., Carcinogenesis 27 (2006): 1655-1660-   Wissing, M. D. et al., Oncotarget. 5 (2014): 7357-7367-   Wong, N. et al., J Hepatol. 38 (2003): 298-306-   Wong, S. Q. et al., Oncotarget. 6 (2015): 1115-1127-   Woo, J. et al., Biochem. Biophys. Res Commun. 367 (2008): 291-298-   Wood, L. M. et al., Cancer Immunol. Immunother. 61 (2012): 689-700-   Wright, D. G. et al., Anticancer Res 16 (1996): 3349-3351-   Wrzeszczynski, K. O. et al., PLoS. One. 6 (2011): e28503-   Wu, C. et al., BMC. Bioinformatics. 13 (2012a): 182-   Wu, C. C. et al., Proteomics. Clin Appl. 2 (2008): 1586-1595-   Wu, C. C. et al., Biochim. Biophys. Acta 1823 (2012b): 2227-2236-   Wu, C. Y. et al., J Biomed. Sci. 18 (2011a): 1-   Wu, H. et al., Nat Med. 17 (2011 b): 347-355-   Wu, H. C. et al., Nat Commun. 5 (2014a): 3214-   Wu, J. et al., Oncogene 31 (2012c): 333-341-   Wu, J. et al., ACS Chem Biol 8 (2013a): 2201-2208-   Wu, M. Z. et al., Cancer Res 75 (2015): 3912-3924-   Wu, T. et al., Hepatology 36 (2002): 363-373-   Wu, T. T. et al., Chin J Physiol 49 (2006): 192-198-   Wu, W. et al., Cancer Res 67 (2007): 951-958-   Wu, X. et al., Hum. Mol. Genet. 21 (2012d): 456-462-   Wu, Y. et al., Biomed. Res 33 (2012e): 75-82-   Wu, Y. et al., Cancer Sci. 103 (2012f): 1820-1825-   Wu, Y. et al., Cell Rep. 5 (2013b): 224-236-   Wu, Y. et al., J Surg. Oncol 105 (2012g): 724-730-   Wu, Z. et al., Neoplasia. 11 (2009): 66-76-   Wu, Z. et al., Breast Cancer Res 16 (2014b): R75-   Wu, Z. B. et al., J Immunol. Res 2014 (2014c): 131494-   Wu, Z. Y. et al., Scand. J Immunol. 74 (2011c): 561-567-   Wurdak, H. et al., Cell Stem Cell 6 (2010): 37-47-   Xia, Luo et al., Reprod. Sci. 17 (2010): 791-797-   Xia, Q. S. et al., Zhonghua Yi. Xue. Za Zhi. 91 (2011): 554-559-   Xiang, X. et al., PLoS. One. 7 (2012): e50781-   Xiang, Y. J. et al., PLoS. One. 9 (2014): e109449-   Xiao, F. et al., Hum. Genet. 133 (2014): 559-574-   Xiao, J. et al., J Biol. Chem. 276 (2001): 6105-6111-   Xiao, W. et al., Nucleic Acids Res 26 (1998): 3908-3914-   Xiao, X. et al., J Transl. Med. 11 (2013): 151-   Xin, B. et al., Oncogene 24 (2005): 724-731-   Xin, H. et al., Oncogene 22 (2003): 4831-4840-   Xin, Z. et al., Virchows Arch. 465 (2014): 35-47-   Xing, Q. T. et al., Onco. Targets. Ther. 7 (2014): 881-885-   Xu, C. et al., Biomarkers 20 (2015a): 271-274-   Xu, C. Z. et al., Int. J Clin Exp. Pathol. 6 (2013a): 2745-2756-   Xu, H. et al., J Clin Oncol 30 (2012): 751-757-   Xu, J. et al., Oncol Rep. 34 (2015b): 1424-1430-   Xu, L. et al., Zhongguo Fei. Ai. Za Zhi. 14 (2011): 727-732-   Xu, W. et al., Med. Oncol 32 (2015c): 96-   Xu, X. et al., IUBMB. Life 65 (2013b): 873-882-   Xu, X. et al., Zhonghua Bing. Li Xue. Za Zhi. 43 (2014a): 177-183-   Xu, Y. et al., PLoS. One. 9 (2014b): e100127-   Xu, Y. et al., PLoS. One. 8 (2013c): e64973-   Xu, Y. et al., Oncol Lett. 7 (2014c): 1474-1478-   Xu, Y. F. et al., BMC. Cancer 15 (2015d): 332-   Xu, Z. et al., Leuk. Res 33 (2009): 891-897-   Xu, Z. et al., Anat. Rec. (Hoboken.) 295 (2012): 1446-1454-   Xue, L. Y. et al., Zhonghua Zhong. Liu Za Zhi. 32 (2010): 838-844-   Yakimchuk, K. et al., Mol. Cell Endocrinol. 375 (2013): 121-129-   Yamada, H. et al., Genes Chromosomes. Cancer 47 (2008): 810-818-   Yamada, H. Y. et al., Oncogene 25 (2006): 1330-1339-   Yamada, R. et al., Tissue Antigens 81 (2013): 428-434-   Yamada, Y. et al., Jpn. J Cancer Res 90 (1999): 987-992-   Yamamoto, S. et al., Ann. Surg. Oncol 14 (2007): 2141-2149-   Yamashita, J. et al., Acta Derm. Venereol. 92 (2012): 593-597-   Yamauchi, T. et al., Environ. Health Prev. Med. 19 (2014): 265-270-   Yamazaki, M. et al., Lab Invest 94 (2014): 1260-1272-   Yamazoe, S. et al., J Exp. Clin Cancer Res 29 (2010): 53-   Yan, C. et al., J Ovarian. Res 7 (2014a): 78-   Yan, H. X. et al., J Biol Chem 281 (2006): 15423-15433-   Yan, L. et al., Tumour. Biol 34 (2013a): 4089-4100-   Yan, Q. et al., Mol. Cell Biol 33 (2013b): 845-857-   Yan, X. et al., Int. J Clin Exp. Pathol. 7 (2014b): 8715-8723-   Yan, X. B. et al., Mol. Med. Rep. 10 (2014c): 2720-2728-   Yan, Y. et al., PLoS. One. 8 (2013c): e81905-   Yang, H. et al., Cancer Res 68 (2008a): 2530-2537-   Yang, H. Y. et al., J Proteomics. 75 (2012a): 3639-3653-   Yang, J. et al., Neurosurg. Clin N. Am. 23 (2012b): 451-458-   Yang, J. et al., Cell Biochem. Biophys. 70 (2014a): 1943-1949-   Yang, J. J. et al., Blood 120 (2012c): 4197-4204-   Yang, J. L. et al., Int. J Cancer 89 (2000): 431-439-   Yang, P. et al., Mol. Cell Biol 32 (2012d): 3121-3131-   Yang, P. et al., Curr. Pharm. Des 21 (2015a): 1292-1300-   Yang, P. et al., Zhonghua Yi. Xue. Za Zhi. 93 (2013): 5-7-   Yang, T. et al., Tumour. Biol 35 (2014b): 11199-11207-   Yang, T. et al., J Biol Chem 278 (2003): 15291-15296-   Yang, W. et al., Mol. Med. Rep. 10 (2014c): 1205-1214-   Yang, X. et al., Pathol. Oncol Res 20 (2014d): 641-648-   Yang, Y. et al., Biochem. Biophys. Res Commun. 332 (2005): 181-187-   Yang, Y. et al., Biochem. Biophys. Res Commun. 450 (2014e): 899-905-   Yang, Y. et al., Cancer Discov 4 (2014f): 480-493-   Yang, Y. et al., Exp. Oncol 30 (2008b): 81-87-   Yang, Y. et al., Mol. Cell 58 (2015b): 47-59-   Yang, Y. L. et al., Leuk. Res 34 (2010): 18-23-   Yang, Y. M. et al., Cancer Sci. 102 (2011): 1264-1271-   Yang, Z. et al., Int. J Med. Sci. 12 (2015c): 256-263-   Yao, J. et al., Cancer Immunol. Res. 2 (2014a): 371-379-   Yao, X. et al., Biochem. Biophys. Res Commun. 455 (2014b): 277-284-   Yao, Y. S. et al., Clin Transl. Sci. 8 (2015): 137-142-   Yasen, M. et al., Clin Cancer Res 11 (2005): 7354-7361-   Yasen, M. et al., Int. J Oncol 40 (2012): 789-797-   Ye, C. et al., J Neurochem. 133 (2015): 273-283-   Ye, Z. et al., Int. J Clin Exp. Med. 8 (2015): 3707-3715-   Yeates, L. C. et al., Biochem. Biophys. Res Commun. 238 (1997):    66-70-   Yeh, I. et al., Am. J Surg. Pathol. 39 (2015): 581-591-   Yeh, S. et al., Proc. Natl. Acad. Sci. U.S.A 97 (2000): 11256-11261-   Yen, L. C. et al., Clin Cancer Res 15 (2009): 4508-4513-   Yi, C. H. et al., Cancer Lett. 284 (2009): 149-156-   Yildiz, M. et al., Blood 125 (2015): 668-679-   Yin, B. W. et al., Cancer Immun. 8 (2008): 3-   Yin, J. et al., Med. Oncol 31 (2014): 272-   Yiu, G. K. et al., J Biol Chem 281 (2006): 12210-12217-   Yokota, T. et al., Acta Neuropathol. 111 (2006): 29-38-   Yonezawa, S. et al., Pathol. Int. 49 (1999): 45-54-   Yongjun Zhang, M. M. et al., J Cancer Res Ther. 9 (2013): 660-663-   Yoo, K. H. et al., Oncol Lett. 8 (2014): 2135-2139-   Yoon, D. H. et al., Eur. J Haematol. 88 (2012): 292-305-   Yoon, S. Y. et al., Biochem. Biophys. Res Commun. 326 (2005): 7-17-   Yoshida, A. et al., Am. J Surg. Pathol. 38 (2014): 552-559-   Yoshida, K. et al., Cancer Sci. 104 (2013): 171-177-   Yoshida, Y. et al., Genes Dev. 17 (2003): 1201-1206-   Yoshizawa, A. et al., Clin Cancer Res 16 (2010): 240-248-   Young, A. N. et al., Am. J Pathol. 158 (2001): 1639-1651-   Yu, C. J. et al., Int. J Cancer 69 (1996): 457-465-   Yu, J. et al., Cancer 88 (2000): 1801-1806-   Yu, L. et al., Cancer Res 75 (2015a): 1275-1286-   Yu, M. et al., Oncogene 24 (2005): 1982-1993-   Yu, W. et al., Carcinogenesis 29 (2008): 1717-1724-   Yu, X. et al., Tumour. Biol 36 (2015b): 967-972-   Yu, X. F. et al., World J Gastroenterol. 17 (2011): 4711-4717-   Yu, Z. et al., Mol. Med. Rep. 10 (2014): 1583-1589-   Yuan, B. et al., Cancer Sci. 106 (2015): 819-824-   Yuan, J. Y. et al., Oncol Lett. 1 (2010): 649-655-   Yuan, Y. et al., Am. J Surg. Pathol. 33 (2009): 1673-1682-   Zage, P. E. et al., Cancer 119 (2013): 915-923-   Zagryazhskaya, A. et al., Oncotarget. 6 (2015): 12156-12173-   Zamkova, M. et al., Cell Cycle 12 (2013): 826-836-   Zang, H. et al., Zhonghua Shi Yan. He. Lin. Chuang. Bing. Du Xue. Za    Zhi. 26 (2012): 285-287-   Zapatero, A. et al., Urol. Oncol 32 (2014): 1327-1332-   Zaravinos, A. et al., Tumour. Biol 35 (2014): 4987-5005-   Zaremba, S. et al., Cancer Res. 57 (1997): 4570-4577-   Zarubin, T. et al., Cell Res 15 (2005): 439-446-   Zekri, A. et al., Oncol Res 20 (2012): 241-250-   Zekri, A. R. et al., Asian Pac. J Cancer Prev. 16 (2015): 3543-3549-   Zeng, X. et al., Ai. Zheng. 26 (2007): 1080-1084-   Zhai, W. et al., Eur. Rev Med. Pharmacol. Sci. 18 (2014): 1354-1360-   Zhan, X. et al., Anal. Biochem. 354 (2006): 279-289-   Zhang, B. et al., J Huazhong. Univ Sci. Technolog. Med. Sci. 30    (2010a): 322-325-   Zhang, C. et al., J Surg. Res 197 (2015a): 301-306-   Zhang, C. et al., BMC. Gastroenterol. 15 (2015b): 49-   Zhang, C. Y. et al., Asian J Androl 17 (2015c): 106-110-   Zhang, F. et al., J Viral Hepat. 21 (2014a): 241-250-   Zhang, F. et al., Cancer Res 63 (2003): 5005-5010-   Zhang, G. et al., Oncol Rep. 33 (2015d): 1147-1154-   Zhang, H. et al., Tumour. Biol 36 (2015e): 997-1002-   Zhang, H. et al., Nat Genet. 42 (2010b): 755-758-   Zhang, H. H. et al., Int. J Clin Exp. Pathol. 6 (2013a): 1734-1746-   Zhang, J. et al., Hum. Pathol. 46 (2015f): 1331-1340-   Zhang, J. et al., Tumour. Biol 36 (2015g): 2163-2168-   Zhang, J. et al., PLoS. One. 9 (2014b): e109318-   Zhang, K. et al., Tumour. Biol 35 (2014c): 4031-4040-   Zhang, L. et al., Med. Oncol 32 (2015h): 454-   Zhang, L. et al., Mol. Cancer Ther. 6 (2007): 1661-1672-   Zhang, L. et al., J Cell Mol. Med. 19 (2015i): 799-805-   Zhang, L. et al., Cancer Res 65 (2005a): 925-932-   Zhang, M. et al., J Exp. Clin Cancer Res 34 (2015j): 60-   Zhang, M. et al., Cancer Lett. 243 (2006): 38-46-   Zhang, N. et al., Oncotarget. (2016a)-   Zhang, P. et al., Genome 57 (2014d): 253-257-   Zhang, S. Q. et al., Mol. Med. Rep. 12 (2015k): 1177-1182-   Zhang, W. et al., Epigenetics. 10 (2015i): 736-748-   Zhang, W. et al., Acta Haematol. 130 (2013b): 297-304-   Zhang, W. et al., Tumour. Biol (2015m)-   Zhang, W. et al., J Biol Chem 286 (2011): 35899-35905-   Zhang, W. et al., Biochem. J (2016b)-   Zhang, X. et al., Oncotarget. 5 (2014e): 6178-6190-   Zhang, X. et al., PLoS. One. 8 (2013c): e72458-   Zhang, X. et al., Leuk. Res 39 (2015n): 1448-1454-   Zhang, Y. et al., Clin Lung Cancer 14 (2013d): 45-49-   Zhang, Y. et al., PLoS. One. 9 (2014f): e90154-   Zhang, Y. J. et al., Cancer Lett. 275 (2009): 277-284-   Zhang, Y. X. et al., Biomed. Pharmacother. 67 (2013e): 97-102-   Zhang, Z. et al., Gynecol. Oncol 135 (2014g): 69-73-   Zhang, Z. et al., Cancer Epidemiol. Biomarkers Prev. 14 (2005b):    1188-1193-   Zhang, Z. et al., J Biol Chem 290 (2015o): 19558-19568-   Zhao, C. et al., Neoplasia. 9 (2007): 1-7-   Zhao, C. et al., Endocrine. 36 (2009): 224-232-   Zhao, H. et al., Cancer Gene Ther. 21 (2014a): 448-455-   Zhao, H. et al., Cell Tissue Res (2015a)-   Zhao, H. et al., Zhonghua Gan Zang. Bing. Za Zhi. 10 (2002): 100-102-   Zhao, Q. et al., Exp. Ther. Med. 5 (2013a): 942-946-   Zhao, X. et al., Cancer Res 65 (2005): 2125-2129-   Zhao, X. et al., Onco. Targets. Ther. 7 (2014b): 343-351-   Zhao, X. et al., Lab Invest 93 (2013b): 8-19-   Zhao, Y. et al., Onco. Targets. Ther. 8 (2015b): 421-425-   Zhao, Y. et al., Hum. Pathol. 44 (2013c): 365-373-   Zhao, Z. et al., Eur. J Surg. Oncol 40 (2014c): 1361-1368-   Zhao, Z. et al., RNA. Biol 12 (2015c): 538-554-   Zhao, Z. K. et al., Tumour. Biol. 34 (2013d): 173-180-   Zheng, C. X. et al., Int. J Oncol 43 (2013): 755-764-   Zheng, M. et al., Ai. Zheng. 23 (2004): 771-776-   Zhou, B. et al., Cancer Biol. Ther 13 (2012a): 871-879-   Zhou, D. et al., Cancer Cell 16 (2009): 425-438-   Zhou, D. et al., PLoS. One. 8 (2013a): e53310-   Zhou, J. et al., Lung Cancer 14 (1996): 85-97-   Zhou, J. et al., J Biol Chem 285 (2010): 40342-40350-   Zhou, J. et al., J Surg. Res 188 (2014a): 129-136-   Zhou, J. B. et al., Mol. Med. Rep. 7 (2013b): 591-597-   Zhou, J. R. et al., Zhonghua Er. Bi Yan. Hou Tou. Jing. Wai Ke. Za    Zhi. 42 (2007): 934-938-   Zhou, L. et al., Clin Transl. Oncol 16 (2014b): 906-913-   Zhou, T. B. et al., J Recept. Signal. Transduct. Res 33 (2013):    28-36-   Zhou, X. et al., Arch. Med. Res 42 (2011): 589-595-   Zhou, X. et al., Oncotarget. 6 (2015a): 41077-41091-   Zhou, Y. et al., Am. J Clin Pathol. 138 (2012b): 744-750-   Zhou, Z. et al., Exp. Cell Res 331 (2015b): 399-407-   Zhu, F. et al., Zhongguo Shi Yan. Xue. Ye. Xue. Za Zhi. 21 (2013a):    396-398-   Zhu, J. et al., Asian Pac. J Cancer Prev. 14 (2013b): 3011-3015-   Zhu, J. et al., Oncogene (2015)-   Zhu, M. et al., Nucleic Acids Res 42 (2014a): 13074-13081-   Zhu, Q. et al., Mol. Cell Biol 27 (2007): 324-339-   Zhu, S. et al., FEBS Lett. 588 (2014b): 981-989-   Zhu, X. et al., Gynecol. Oncol 112 (2009): 248-256-   Zhu, Z. et al., Carcinogenesis 35 (2014c): 1901-1910-   Zi, Y. et al., Int. J Clin Exp. Pathol. 8 (2015): 1312-1320-   Ziebarth, J. D. et al., PLoS. One. 7 (2012): e47137-   Zighelboim, I. et al., Clin Cancer Res 13 (2007): 2882-2889-   Zighelboim, I. et al., J Clin Oncol 27 (2009): 3091-3096-   Zins, K. et al., Int. J Mol. Sci. 16 (2015): 29643-29653-   Zohrabian, V. M. et al., Oncol Rep. 18 (2007): 321-328-   Zou, C. et al., Cancer 118 (2012): 1845-1855-   Zou, J. X. et al., Mol. Cancer Res 12 (2014a): 539-549-   Zou, S. et al., Nat Commun. 5 (2014b): 5696-   Zou, T. T. et al., Oncogene 21 (2002): 4855-4862-   Zou, W. et al., Cancer Sci. 101 (2010): 2156-2162-   Zou, Y. et al., Biomed. Rep. 3 (2015): 33-37-   Zubor, P. et al., Mol. Biol. Rep. 42 (2015): 977-988-   Zuo, G. W. et al., Histol. Histopathol. 25 (2010): 795-806

The invention claimed is:
 1. A method of treating a patient who hascancer, comprising administering to said patient a compositioncomprising a population of activated T cells that kill cancer cells inthe patient that express a peptide, wherein said peptide consists of theamino acid sequence of SLLELDGINL (SEQ ID NO: 72), wherein said canceris ovarian cancer, non-small cell lung cancer, small cell lung cancer,prostate cancer, breast cancer, or uterine cancer.
 2. The method ofclaim 1, wherein the T cells are autologous to the patient.
 3. Themethod of claim 1, wherein the composition further comprises an adjuvantselected from anti-CD40 antibody, imiquimod, resiquimod, GM-CSF,cyclophosphamide, sunitinib, bevacizumab, interferon-alpha,interferon-beta, CpG oligonucleotides and derivatives, poly-(I:C) andderivatives, RNA, sildenafil, particulate formulations with poly(lactideco-glycolide) (PLG), virosomes, interleukin (IL)-1, IL-2, IL-4, IL-7,IL-12, IL-13, IL-15, IL-21, and IL-23.
 4. The method of claim 1, whereinthe activated T cells are cytotoxic T cells produced by contacting Tcells with an antigen presenting cell that presents the peptide in acomplex with an MHC class I molecule on the surface of the antigenpresenting cell, for a period of time sufficient to activate said T cellspecifically against the peptide.
 5. The method of claim 1, wherein thecancer is ovarian cancer.
 6. The method of claim 1, wherein the canceris non-small cell lung cancer.
 7. The method of claim 1, wherein thecancer is small cell lung cancer.
 8. The method of claim 1, wherein thecancer is prostate cancer.
 9. The method of claim 1, wherein the canceris breast cancer.
 10. The method of claim 1, wherein the cancer isuterine cancer.
 11. A method of eliciting an immune response in apatient who has cancer, comprising administering to said patient acomposition comprising a population of activated T cells that killcancer cells in the patient that express a peptide, wherein said peptideconsists of the amino acid sequence of SLLELDGINL (SEQ ID NO: 72),wherein said cancer is ovarian cancer, non-small cell lung cancer, smallcell lung cancer, prostate cancer, breast cancer, or uterine cancer. 12.The method of claim 11, wherein the T cells are autologous to thepatient.
 13. The method of claim 11, wherein the composition furthercomprises an adjuvant selected from anti-CD40 antibody, imiquimod,resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab,interferon-alpha, interferon-beta, CpG oligonucleotides and derivatives,poly-(I:C) and derivatives, RNA, sildenafil, particulate formulationswith poly(lactide co-glycolide) (PLG), virosomes, interleukin (IL)-1,IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23.
 14. The methodof claim 11, wherein the activated T cells are cytotoxic T cellsproduced by contacting T cells with an antigen presenting cell thatpresents the peptide in a complex with an MHC class I molecule on thesurface of the antigen presenting cell, for a period of time sufficientto activate said T cell specifically against the peptide.
 15. The methodof claim 11, wherein the cancer is ovarian cancer.
 16. The method ofclaim 11, wherein the cancer is non-small cell lung cancer.
 17. Themethod of claim 11, wherein the cancer is small cell lung cancer. 18.The method of claim 11, wherein the cancer is prostate cancer.
 19. Themethod of claim 11, wherein the cancer is breast cancer.
 20. The methodof claim 11, wherein the cancer is uterine cancer.